rs534656527
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):c.14419G>A(p.Ala4807Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
5
6
8
Clinical Significance
Conservation
PhyloP100: 7.71
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_206933.4
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.14419G>A | p.Ala4807Thr | missense_variant | 66/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.14419G>A | p.Ala4807Thr | missense_variant | 66/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.14419G>A | p.Ala4807Thr | missense_variant | 66/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251366Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135856
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GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727246
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4807 of the USH2A protein (p.Ala4807Thr). This variant is present in population databases (rs534656527, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 198366). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 | Eurofins Ntd Llc (ga) | Apr 28, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29343940) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 25, 2015 | The p.Ala4807Thr variant in USH2A has not been previously reported in individual s with hearing loss, but has been identified in 5/66724 European chromosomes and 5/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs534656527). Computational prediction tools a nd conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala4807Thr varian t is uncertain. - |
Usher syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Feb 21, 2024 | The variant NM_206933.4:c.14419G>A in USH2A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 4807 (p.Ala4807Thr). The filtering allele frequency (the upper threshold of the 95% CI of 5/30782) of the c.14419G>A variant in USH2A is 0.00006365 for South Asian chromosomes by gnomAD v2.1.1, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024). - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 14, 2017 | - - |
Usher syndrome type 2A Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at