rs547581739
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):c.3176C>T(p.Pro1059Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1059P) has been classified as Likely benign.
Frequency
Consequence
NM_206933.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.3176C>T | p.Pro1059Leu | missense_variant | 16/72 | ENST00000307340.8 | |
USH2A-AS1 | XR_922596.4 | n.691+11488G>A | intron_variant, non_coding_transcript_variant | ||||
USH2A | NM_007123.6 | c.3176C>T | p.Pro1059Leu | missense_variant | 16/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.3176C>T | p.Pro1059Leu | missense_variant | 16/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.3176C>T | p.Pro1059Leu | missense_variant | 16/21 | 1 | |||
USH2A | ENST00000674083.1 | c.3176C>T | p.Pro1059Leu | missense_variant | 16/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251116Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135706
GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727152
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74450
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 20, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinitis pigmentosa Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1059 of the USH2A protein (p.Pro1059Leu). This variant is present in population databases (rs547581739, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome and/or retinitis pigmentosa (PMID: 15325563, 22952768, 31456290). ClinVar contains an entry for this variant (Variation ID: 552332). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2020 | Observed in patients with Usher syndrome or retinitis pigmentosa in published literature; however, no specific patient information was provided and Licastro et al. reported no second USH2A variant in the published patient (Seyedahmadi et al., 2004; Licastro et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31456290, 20507924, 22952768, 15325563) - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 08, 2017 | - - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at