Table 2.
Variants in reported risk genes identified in 38 patients with UIA and/or aSAH
| Gene gnomAD constraint metrics | Transcript ID | c. notation p. notation | dbSNP rs ID ClinVar allele ID | Classificationa | gnomAD all MAFb het/hom/Σ |
Pathogenicity predictionsc | Subjects | Clinical findings; family history (FH) | |
|---|---|---|---|---|---|---|---|---|---|
| CADD/REVEL/M-CAP/ClinPred | Impact on splicing | ||||||||
|
ADAMTS15 misZ = 0.60 pLI = 0.0 |
NM_139055 |
c.1258G>A p.Gly420Ser |
rs767345140 n.r |
VUSPM1+PP3 |
0.006092% 17/0/279072 |
33/0.506/0.011/0.641 | last nucleotide in exon 3; donor loss (HSF, NG2, MES) | IA83 |
1 IA + 1 aSAH FH neg |
|
ANGPTL6 misZ = 0.64 pLI = 0.0 |
NM_031917 |
c.1072G>A p.Arg358Cys |
rs147149731 n.r |
VUSPM1+BP4 |
1.139% 3221/32/282740 |
13.39/0.238/n.a./0.014 | n.d | IA61 (+ VUSRNF213) |
4 IA + 1 aSAH FH neg |
|
c.287A>G p.Leu96Pro |
rs559282550 n.r |
VUSPP3 |
1.552% 447/4/28796 |
32/0.573/n.a./0.183 | n.d | IA78 (+ 2VUSRNF213) |
1 giant IA FH pos |
||
| IA84 |
1 IA FH pos |
||||||||
|
PCNT misZ = -1.33 pLI = 0.0 |
NM_006031 |
c.959G > A p.Arg320Lys |
rs149844283 194,942 |
VUSPM2+BP1+BP4 |
0.01048% 26/0/248208 |
15.60/0.070/0.003/0.097 | no impact | IA72 |
1 IA + 1 aSAH FH neg |
|
c.2033A>G p.Lys678Arg |
rs149623054 265,806 |
LBVBP1+BP4 |
0.1591% 450/2/282880 |
8.311/0.026/0.012/0.019 | acceptor gain (HSF) | IA85 (+ VUSPCNT) |
4 IA + 1 aSAH FH pos |
||
|
c.2839G>C p.Ala947Pro |
rs1177229119 n.r |
VUSPM2+PP3+BP1 |
0.001595% 4/0/250744 |
20.5/0.093/0.027/0.669 | n.d | IA75 |
1 IA + 1 aSAH FH neg |
||
|
c.4345C>G p.Gln1449Glu |
rs139432601 169,656 |
LBVBP1+BP4 |
0.347% 981/9/282746 |
14.70/0.134/0.011/0.010 | n.d | IA63 (+ transVUSPCNT) |
2 IA + 1 aSAH FH neg |
||
|
c.4354G>A p.Gly1452Arg |
rs143796569 169,657 |
VUSPP3+BP1+BP4 |
0.267% 755/6/282742 |
22.0/0.227/n.a./0.036 | gain of AGGT; donor gain (NG2, BDGP); acceptor gain (HSF) | IA63 (+ transLBVPCNT) |
2 IA + 1 aSAH FH neg |
||
| IA79 (+ VUSRNF213) |
2 IA FH pos |
||||||||
|
c.6404C>T p.Thr2135Met |
rs145710874 n.r |
VUSPM2+BP1+BP4 |
0.001193% 3/0/2514320 |
11.77/0.053/0.002/0.078 | n.d | IA54 (+ VUSTHSD1) |
5 IA FH neg |
||
|
c.6739C>T p.His2247Tyr |
rs61735812 142,330 |
LBVBS4+BP1+BP4 |
1.218% 2866/22/235400 |
1.606/0.038/n.a./0.002 | n.d | IA24d |
1 IA + 1 aSAH FH pos |
||
|
c.7652C>T p.Ala2551Val |
rs12481791 142,308 |
VUSPP3+BP1+BP4 |
1.444% 3848/39/266458 |
22.5/0.109/n.a./0.027 | gain of AGGT; donor gain (HSF, NG2, MES) | IA57 |
4 IA + 2 aSAH FH neg |
||
| IA59 |
1 IA FH pos |
||||||||
|
c.7988G>A p.Arg2663His |
rs778334017 430,519 |
VUSPM2+BP1+BP4 |
0.00115% 2/0/173878 |
15.38/0.042/0.011/0.467 | n.d | IA85 (+ LBVPCNT) |
4 IA + 1 aSAH FH pos |
||
|
RNF213 misZ = 2.64 pLI = 0.0 |
NM_001256071 |
c.397C>A p.Leu133Met |
rs149177904 404,723 |
VUSPP2+BP4 |
0.1089% 231/1/212142 |
7.116/0.047/0.006/0.002 | n.d | IA78 (+ VUSANGPTL6, + VUSRNF213) |
1 giant IA FH pos |
|
c.626T>A p.Ile209Asn |
rs144769597 404,724 |
VUSPP2+BP4 |
0.1151% 323/1/280624 |
0.295/0.165/0.017/0.007 | n.d | IA78 (+ VUSANGPTL6, + VUSRNF213) |
1 giant IA FH pos |
||
|
c.8084C>T p.Ala2695Val |
rs202096577 n.r |
VUSPP2+BP4 |
0.05313% 150/0/282338 |
24.4/0.325/0.018/0.187 | n.d | IA61 (+ VUSANGPTL6) |
4 IA + 1 aSAH FH neg |
||
|
c.14030G>T p.Trp4677Leu |
rs61741961 n.r |
VUSPP2+PP3 |
1.047% 2962/29/282802 |
23.4/0.602/n.a./0.088 | n.d | IA79 (+ VUSPCNT) |
2 IA FH pos |
||
|
THSD1 misZ = 0.49 pLI = 0.0 |
NM_018676 |
c.1666G>C p.Gln556Glu |
rs148515012 n.r |
VUSBP4 |
0.01344% 38/0/282718 |
25.0/0.228/0.041/0.193 | n.d | IA64S481Nr111 |
1 IA FH pos |
|
c.871C>T p.Glu291Lys |
rs41292808 n.r |
VUSBP4 |
1.864% 5271/78/282824 |
12.32/0.090/n.a./0.031 | n.d | IA17 (+ VUSTMEM132B) |
1 IA + 1 aSAH FH neg |
||
| IA49 |
1 IA + 1 AA FH pos |
||||||||
| IA54 (+ VUSPCNT) |
5 IA FH neg |
||||||||
| IA90e |
3 IA FH pos |
||||||||
|
c.592G>C p.Gln198Glu |
rs186046951 n.r |
VUSBP4 |
0.01097% 31/0/282698 |
18.67/0.046/0.007/0.071 | n.d | IA76 |
4 IA FH pos |
||
|
TMEM132B misZ = 1.66 pLI = 1.0 |
NM_052907 |
c.2737C>A p.Leu913Met |
rs61940807 n.r |
VUSPM1+BP4 |
0.9920% 2787/52/280952 |
23.2/0.165/n.a./0.075 | n.d | IA17 (+ VUSTHSD1) |
1 IA + 1 aSAH FH neg |
Variants with MAF ≤ 0.05 (5%) are listed by gene and were detected in 6 out of 8 analyzed genes: ADAMTS15, ANGPTL6, PCNT, RNF213, THSD1 and TMEM132B; no variants were identified in ARHGEF17 and LOXL2. For each gene, gnomAD constraint metrics (v2.1) including missense Z score (misZ; intolerance to variation) and pLI score (probability of loss-of-function intolerance) are given. Transcript IDs correspond to the NCBI Reference Sequence (RefSeq) project. Nucleotide and amino acid changes are given according to the indicated transcript ID. Nucleotide numbering uses + 1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1. Concomitant variants are indicated in the column “Subject” after the patient numbers in parentheses
aSAH aneurysmal subarachnoid hemorrhage, IA intracranial aneurysm (including unruptured and ruptured IA), FH pos. positive family history, FH neg. negative family history, FH n.d. family history not determined, n.r. not reported, n.a. not available, n.d. not determined
aVariant classification: VUS, variant of uncertain significance; LBV, likely benign variant. Classification criteria PM1, PM2, PP3, BS4, BP1 and BP4 are explained in the Supplementary Methods. BP1 (missense variant in a gene for which primarily truncating variants are known to cause disease) was assigned to PCNT variants, because truncating variants in PCNT are the primary type of pathogenic variants for Microcephalic osteodysplastic primordial dwarfism, type II (MIM #210720), a conditions that is associated with IA. RNF213 variants were assigned with PP2 (missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease), because missense variants in RNF213 have been associated with susceptibility to Moyamoya disease 2 (MIM #607151), a disorder associated with intracranial vascular malformations. References see Supplementary Information
bgnomAD, Genome Aggregation Database (v2.1); all MAF, minor allele frequency (total population); het/hom/Σ, number of heterozygous carriers/number of homozygous carriers/total number of analyzed alleles
cDetails on pathogenicity predictors and respective thresholds [CADD (≥ 20), REVEL (≥ 0.5), M-CAP (≥ 0.025), ClinPred (≥ 0.5)] as well as on splice site predictions with HSF, NetGene2 (NG2), MaxEntScan (MES) and BDGP are outlined in the Supplementary Methods
dVariant does not cosegregate with the disease in the family
eVariant was identified in further affected family members