1-216175261-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_206933.4(USH2A):c.4618G>A(p.Asp1540Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,522 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1540E) has been classified as Uncertain significance.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.4618G>A | p.Asp1540Asn | missense_variant | Exon 21 of 72 | 1 | NM_206933.4 | ENSP00000305941.3 | ||
USH2A | ENST00000366942.3 | c.4618G>A | p.Asp1540Asn | missense_variant | Exon 21 of 21 | 1 | ENSP00000355909.3 | |||
USH2A | ENST00000674083.1 | c.4618G>A | p.Asp1540Asn | missense_variant | Exon 21 of 73 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135332
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461344Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 726974
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74336
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 28, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 29, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1540 of the USH2A protein (p.Asp1540Asn). This variant is present in population databases (rs752238803, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 25472526, 28041643, 36785559). ClinVar contains an entry for this variant (Variation ID: 438022). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. 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. - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 28, 2018 | - - |
USH2A-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2024 | The USH2A c.4618G>A variant is predicted to result in the amino acid substitution p.Asp1540Asn. This variant was reported in individuals with retinitis pigmentosa; however, these patients already carried two known pathogenic variants in USH2A (Zhao et al. 2015. PubMed ID: 25472526; supplementary data, Carss et al. 2017. PubMed ID: 28041643). This variant was also described in cis with the c.2276G>T variant in another individual with suspected USH2A-associated disease; an additional causative variant was not identified on the second allele (Reurink et al. 2023. PubMed ID: 36785559). In a large cohort study of individuals with retinal disease, this variant was described as a variant of uncertain significance (supplementary data, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at