Table III.
Selected variants prioritised from the exome sequencing data in severe sperm motility disorders.
| Patient | Gene | cDNA* | Protein | Zygosity | GnomAD variant frequency (population with highest frequency) | Variant classification (ACMG)** | Gene expression enriched in testis*** | Disease model described | Additional information (see also Supplementary Table SI) | Conclusion |
|---|---|---|---|---|---|---|---|---|---|---|
| ARG1 | DNAH12 | c.5393T>C | p.(Phe1798Ser) | Het | 0.1% (AFR: 0.4%) | VUS | Yes | No | Variants have highly similar allele frequencies suggesting they reside on the same allele | Unclear if disease causing |
| c.7438C>T | p.(Pro2480Ser) | Het | 0.0% (AFR: 0.2%) | VUS | ||||||
| ARG2 | CFAP43 | c.1442 + 1G>A | p.? | Het | 0.0% (NFE: 0.0%) | Likely pathogenic | Yes | Yes, mouse (Tang et al., 2017) |
c.1442 + 1G>A is present in trans with c.1040T>C Known gene c.1040T>C previously reported (Coutton et al., 2018) |
Probably disease causing |
| c.1019T>C | p.(Phe340Ser) | Het (in cis with c.1040T>C) | 0.01% (NFE: 0.03%) | Unlikely pathogenic | ||||||
| c.1040T>C | p.(Val347Ala) | Het (in cis with c.1019T>C) | 0.01% (NFE: 0.02%) | VUS | ||||||
| ARG3 | DNAH6 | c.1316 + 1_1316 + 2insC | N/A | Het | 0.0% (NFE: 0.0%) | Likely pathogenic | Yes | Yes, mouse and zebrafish (Li et al., 2016) | Known gene | Probably disease causing |
| c.7762C>T | p.(Arg2588*) | Het | 0.0% (AMR: 0.0%) | Pathogenic | ||||||
| ARG4 | PACRG | c.369T>A | p.(Tyr123*) | Hom | 0.00% | Likely pathogenic | Yes | Yes, mouse (Lorenzetti et al., 2004) | Associated with the development of sperm flagellum (Lorenzetti et al., 2004; Li et al. 2015) | Novel candidate gene |
| ARG5 | CFAP58 | c.1360C>T | p.(Gln454*) | Hom | 0.05% (ASJ: 1.09%) | Pathogenic | Yes | No | In homozygosity region. Variant is relatively common in Ashkenazi Jewish population | Probably disease causing |
| ARG6 | CFAP44 | c.652del | p.(Arg218Aspfs*37) | Hom | 0.03% (ASJ: 0.61%) | Pathogenic | Yes | Yes, mouse (Tang et al., 2017) | Known gene | Disease causing |
| ARG7 | DRC1 | c.238C>T | p.(Arg80*) | Het | 0.00% (FIN: 0.03%) | Pathogenic | Yes | Yes, Chlamydomonas reinhardtii (Wirschell et al., 2013) | Described in primary ciliary dyskinesia (Wirschell et al., 2013; Morimoto et al., 2019a) | Novel candidate gene |
| c.352C>T | p.(Gln118*) | Het | 0.04% (0.07% (NFE) | Pathogenic | ||||||
| ARG8 | DNAH6 | c.2059C>A | p.(Pro687Thr) | Hom | 0.04% (NFE: 0.07%) | VUS | Yes | Yes, mouse and zebrafish (Li et al., 2016) | Known gene | Possible candidate gene |
| ATP2B4 | c.376G>C | p.(Gly126Arg) | Hom | 0.01% (SAS: 0.08%) | VUS | No | Yes, mouse (Schuh et al., 2004) | Mouse displays asthenozoospermia. In homozygosity region | Possible candidate gene | |
| CEP350 | c.229A>G | p.(Arg77Gly) | Hom | 0.34% (ASJ: 0.81%) | VUS | No | No | In homozygosity region | Possible candidate gene | |
| CEP290 | c.5998A>G | p.(Ile2000Val) | Het | 0.02% (NFE: 0.04%) | VUS | No | Yes, mouse (Lancaster et al., 2011) | Described in patients with Leber’s Congenital Amaurosis and asthenozoospermia (Yzer et al., 2012) | Possible candidate gene | |
| c.1092T>G | p.(Ile364Met) | Het | 0.08% (SAS: 0.35%) | VUS | ||||||
| ARG9 | CFAP44 | c.2674A>G | p.(Met892Val) | Het | 0.05% (AMR: 0.08%) | Likely benign | Yes | Yes, mouse (Tang et al., 2017) | Known gene | Probably disease causing |
| c.2107A>G | p.(Arg703Gly) | Het | 0.00% | VUS | ||||||
| c.2104A>T | p.(Ile702Leu) | Het | 0.00% | Likely benign | ||||||
| c.1174T>C | p.(Trp392Arg) | Het | 0.00% | VUS | ||||||
| AUS1 | - | – | – | – | – | – | – | – | – | No candidate genes found |
| AUS2 | DNAH1 | c.5105G>A | p.(Arg1702Gln) | Het | 0.00% (NFE: 0.00%) | VUS | No | Yes, mouse (Neesen et al., 2001) | Known gene | Probably disease causing |
| c.10823 + 1G>C | p.? | Het | 0.00% | Likely pathogenic | ||||||
| AUS3 | - | – | – | – | – | – | – | – | – | No candidate genes found |
| AUS4 | SPPL2C | c.634C>T | p.(Arg212Trp) | Hom | 0.01% (SAS: 0.06) | VUS | Yes | Yes, mouse (Niemeyer et al., 2019) | SPPL2c deficiency leads to a partial loss of elongated spermatids and reduced motility of mature spermatozoa, but preserved fertility in mice (Niemeyer et al., 2019). Possibly involved in acrosome formation (Papadopoulou et al., 2019) | Novel candidate gene |
| AUS5 | QRICH2 | c.145dup | p.(Thr49Asnfs*31) | Hom | 0.00% (NFE: 0.00%) | Pathogenic | Yes | Yes, mouse (Shen et al., 2019) | Known gene | Disease causing |
| AUS6 | - | – | – | – | – | – | – | – | – | No candidate genes found |
| AUS7 | TPTE2 | c.715C>T | p.(Gln239*) | Hom | 0.00% (NFE: 0.19%) | Likely pathogenic | Yes | No | Voltage-sensitive phosphatase (Halaszovich et al., 2012) | Novel candidate gene |
| AUS8 | CFAP43 | c.335A>T | p.(Asp112Val) | Hom | 0.01% (NFE : 0.01%) | VUS | Yes | Yes, mouse (Tang et al., 2017) | Known gene In homozygosity region | Probably disease causing |
| AUS9 | CFAP43 | c.944del | p.(Gly315Alafs*22) | Hom | 0.00% | Pathogenic | Yes | Yes, mouse (Tang et al., 2017) | Known gene. In homozygosity region | Disease causing |
| AUS10 | - | – | – | – | – | – | – | – | – | No candidate genes found |
| AUS11 | MDC1 | c.472C>T | p.(Gln158*) | Het | 0.00% | Likely pathogenic | Yes | Yes, mouse (Lou et al., 2006) | Mouse knock-out possibly has a meiotic defect (Lou et al., 2006) | Novel candidate gene |
| c.2134C>T | p.(Gln712*) | Het | 0.00% | Likely pathogenic | ||||||
| AUS12 | QRICH2 | c.169G>A | p.(Glu57Lys) | Hom | 0.01% (NFE: 0.02) | VUS | Yes | Yes, mouse (Shen et al., 2019) | Known gene. In homozygosity region | Probably disease causing |
*
gDNA position and transcript information are available in Supplementary Table SIII.
**
VUS: Variant of Unknown Significance.
***
Based on the Human Protein Atlas version 19.1.
The full table is available in Supplementary Table SIII.