rs202174251
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_153676.4(USH1C):c.1136G>A(p.Gly379Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G379G) has been classified as Likely benign.
Frequency
Consequence
NM_153676.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_153676.4 | c.1136G>A | p.Gly379Asp | missense_variant | 14/27 | ENST00000005226.12 | |
USH1C | NM_005709.4 | c.1136G>A | p.Gly379Asp | missense_variant | 14/21 | ENST00000318024.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.1136G>A | p.Gly379Asp | missense_variant | 14/27 | 5 | NM_153676.4 | ||
USH1C | ENST00000318024.9 | c.1136G>A | p.Gly379Asp | missense_variant | 14/21 | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251490Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135918
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461814Hom.: 0 Cov.: 47 AF XY: 0.0000825 AC XY: 60AN XY: 727216
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 379 of the USH1C protein (p.Gly379Asp). This variant is present in population databases (rs202174251, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 21203349). ClinVar contains an entry for this variant (Variation ID: 47975). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 04, 2020 | The p.Gly379Asp variant in USH1C has been reported in one family with Usher syndrome; however, a second USH1C variant was not identified on the other allele (Aparisi 2010). It has also been identified by our laboratory in 1 proband with hearing loss who had an alternate genetic etiology identified. This variant is present in 0.02% (22/129188) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and it has been reported in ClinVar (Variation ID 47975). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3. - |
Usher syndrome type 1C Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at