rs768813865
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_206933.4(USH2A):āc.1541T>Cā(p.Ile514Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,174 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).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 0.000011 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
6
6
7
Clinical Significance
Conservation
PhyloP100: 8.63
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.834
PP5
Variant 1-216323483-A-G is Pathogenic according to our data. Variant chr1-216323483-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551502.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1541T>C | p.Ile514Thr | missense_variant | 8/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1541T>C | p.Ile514Thr | missense_variant | 8/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1541T>C | p.Ile514Thr | missense_variant | 8/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1541T>C | p.Ile514Thr | missense_variant | 8/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1541T>C | p.Ile514Thr | missense_variant | 8/73 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151876Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250722Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135466
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461298Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726958
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151876Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74168
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 514 of the USH2A protein (p.Ile514Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25649381, 29953849, 33089500; Invitae). ClinVar contains an entry for this variant (Variation ID: 551502). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 13, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 10, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;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