rs142095945
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_206933.4(USH2A):c.12332C>T(p.Ser4111Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S4111S) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.12332C>T | p.Ser4111Phe | missense_variant | 63/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.12332C>T | p.Ser4111Phe | missense_variant | 63/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.12332C>T | p.Ser4111Phe | missense_variant | 63/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250582Hom.: 0 AF XY: 0.0000960 AC XY: 13AN XY: 135436
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461834Hom.: 0 Cov.: 37 AF XY: 0.0000701 AC XY: 51AN XY: 727218
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74324
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.12332C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Retinitis pigmentosa 39 (MIM#613809) and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in two patients with inherited retinal dystrophy (PMID: 32037395, 33623043) and both classified as VUS. It has also been reported as VUS and pathogenic in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 4111 of the USH2A protein (p.Ser4111Phe). This variant is present in population databases (rs142095945, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of USH2A-related conditions ‚Äã (PMID: 30902645, 32037395; Invitae). 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: 48396). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 08, 2011 | Variant classified as Uncertain Significance - Favor Benign. The Ser4111Phe vari ant in USH2A has not been reported in the literature; however, this variant has been identified by our laboratory in two other individual with hearing loss; nei ther of whom had a second USH2A variant. Computational analyses (biochemical ami no acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. In summary, the clinical significance of t his variant cannot be determined with certainty at this time; however, based upo n this data we would lean towards a more likely benign interpretation. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 22, 2021 | - - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Genetics, Fundacion Jimenez Diaz University Hospital | - | This variant is present in population databases (rs142095945, gnomAD_exomes 0.008%), missense variant in a gene that has a low rate of benign missense variation, predicted benign by in-silico pathogenicity predictors. (ACMG: PM2 Moderate, PP2 Supporting, BP4 Supporting). Found in trans with variant NM_206933:c.12332C>T) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at