17-74923046-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_173477.5(USH1G):c.28C>T(p.Arg10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,526 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_173477.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1G | NM_173477.5 | c.28C>T | p.Arg10Trp | missense_variant | 1/3 | ENST00000614341.5 | |
USH1G | NM_001282489.3 | c.-229C>T | 5_prime_UTR_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1G | ENST00000614341.5 | c.28C>T | p.Arg10Trp | missense_variant | 1/3 | 1 | NM_173477.5 | P1 | |
OTOP2 | ENST00000580223.2 | c.-231+12G>A | intron_variant | 1 | |||||
USH1G | ENST00000579243.1 | c.28C>T | p.Arg10Trp | missense_variant, NMD_transcript_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1433526Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1AN XY: 709504
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH1G protein function. ClinVar contains an entry for this variant (Variation ID: 1036695). This missense change has been observed in individual(s) with Usher syndrome type 1, however, in that individual pathogenic alleles were also identified in the PCDH15 gene, which suggests that this c.28C>T variant was not the primary cause of disease (PMID: 24618850). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 10 of the USH1G protein (p.Arg10Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at