1-216325408-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_206933.4(USH2A):āc.1040A>Gā(p.Asp347Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,854 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D347H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1040A>G | p.Asp347Gly | missense_variant | 6/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1040A>G | p.Asp347Gly | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1040A>G | p.Asp347Gly | missense_variant | 6/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1040A>G | p.Asp347Gly | missense_variant | 6/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1040A>G | p.Asp347Gly | missense_variant | 6/73 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250968Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135606
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461658Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727124
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 347 of the USH2A protein (p.Asp347Gly). This variant is present in population databases (rs762384558, gnomAD 0.0009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25558175, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554336). 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 USH2A protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 16, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at