7-107661644-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong
The NM_000441.2(SLC26A4):āc.3G>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000192 in 1,562,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000441.2 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152276Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000142 AC: 2AN: 1410240Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 698074
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74394
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:4
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Variant summary: SLC26A4 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31384 control chromosomes (gnomAD). c.3G>C has been reported in the literature in two compound heterozygous individuals (siblings) affected with Pendred Syndrome in one family (Banghova_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:2
This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs786204426, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). ClinVar contains an entry for this variant (Variation ID: 188721). For these reasons, this variant has been classified as Pathogenic. -
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17876604) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at