17-74919463-T-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_173477.5(USH1G):c.1373A>T(p.Asp458Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,606,924 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 (★★).
Frequency
Consequence
NM_173477.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH1G | NM_173477.5 | c.1373A>T | p.Asp458Val | missense_variant | Exon 2 of 3 | ENST00000614341.5 | NP_775748.2 | |
USH1G | NM_001282489.3 | c.1064A>T | p.Asp355Val | missense_variant | Exon 2 of 3 | NP_001269418.1 | ||
USH1G | XM_011524296.2 | c.1064A>T | p.Asp355Val | missense_variant | Exon 2 of 3 | XP_011522598.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH1G | ENST00000614341.5 | c.1373A>T | p.Asp458Val | missense_variant | Exon 2 of 3 | 1 | NM_173477.5 | ENSP00000480279.1 | ||
USH1G | ENST00000579243.1 | n.*972A>T | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 | ENSP00000462568.1 | ||||
USH1G | ENST00000579243.1 | n.*972A>T | 3_prime_UTR_variant | Exon 2 of 3 | 2 | ENSP00000462568.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151656Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240980Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132704
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1455268Hom.: 0 Cov.: 41 AF XY: 0.00000553 AC XY: 4AN XY: 723548
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151656Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74032
ClinVar
Submissions by phenotype
Usher syndrome type 1G Pathogenic:2
This variant was identified in an homozygous state in a young female patient profound hearing loss. It was inherited from both parents (asymptomatic heterozygous carriers). -
Pathogenic by Deafness Variation Database based on PMID: 16283141 -
not provided Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 458 of the USH1G protein (p.Asp458Val). This variant is present in population databases (rs397517925, gnomAD 0.002%). This missense change has been observed in individual(s) with atypical Usher syndrome (PMID: 16283141, 28944237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48127). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt USH1G protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects USH1G function (PMID: 20142502). For these reasons, this variant has been classified as Pathogenic. -
Rare genetic deafness Pathogenic:1
The Asp458Val variant in USH1G has been identified as a homozygous variant in tw o Turkish probands with moderate to severe and profound hearing loss and was als o detected in 1/498 Turkish control chromosomes (Kalay 2005). In addition, the v ariant was also homozygous in four affected relatives of these probands, and 18 unaffected relatives were either heterozygous for the variant or were wild-type. The affected individuals in these two families were not reported to have vestib ular dysfunction, and did not report visual problems; however funduscopy suggest ed mild retinitis pigmentosa. Electroretinograms were not performed in affected individuals (Kalay 2005). In summary, this variant is likely to be pathogenic, t hough additional studies are required to fully establish its clinical significan ce. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at