rs727503444
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153700.2(STRC):c.3670C>T(p.Arg1224*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000696 in 1,609,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_153700.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000469 AC: 7AN: 149340Hom.: 0 Cov.: 21
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250780Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135586
GnomAD4 exome AF: 0.0000719 AC: 105AN: 1460542Hom.: 1 Cov.: 32 AF XY: 0.0000826 AC XY: 60AN XY: 726630
GnomAD4 genome AF: 0.0000469 AC: 7AN: 149340Hom.: 0 Cov.: 21 AF XY: 0.0000274 AC XY: 2AN XY: 72954
ClinVar
Submissions by phenotype
STRC-related disorder Pathogenic:1
The STRC c.3670C>T variant is predicted to result in premature protein termination (p.Arg1224*). This variant was reported in the homozygous or compound heterozygous state with another STRC pathogenic variant in multiple individuals with autosomal recessive hearing loss (Table S1, Liu et al. 2019. PubMed ID: 31216405; Nishio et al. 2022. PubMed ID: 35022556; Amr et al. 2018. PubMed ID: 29339441; https://www.ncbi.nlm.nih.gov/clinvar/variation/165315/). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in STRC are expected to be pathogenic. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21078986, 22147502, 31216405, 29339441) -
Rare genetic deafness Pathogenic:1
The p.Arg1224X variant in STRC has been previously identified by our laboratory in 2 Caucasian individuals with hearing loss, both of whom carried a second path ogenic variant in STRC on the other allele. It was absent from large population studies. This nonsense variant leads to a premature termination codon at positio n 1224, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based on its predicted impact to the protein. -
Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at