1-215650755-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_206933.4(USH2A):​c.14180G>A​(p.Trp4727*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

USH2A
NM_206933.4 stop_gained

Scores

3
2
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.776
Variant links:
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 Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-215650755-C-T is Pathogenic according to our data. Variant chr1-215650755-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215650755-C-T is described in Lovd as [Pathogenic]. Variant chr1-215650755-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.14180G>A p.Trp4727* stop_gained Exon 65 of 72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.14180G>A p.Trp4727* stop_gained Exon 65 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.14180G>A p.Trp4727* stop_gained Exon 65 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:2
Mar 18, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
May 11, 2018
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Aug 04, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp4727*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 25649381, 29912909). 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: 48429). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1
Mar 06, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Trp4727X variant in USH2A has not been reported in the literature nor previo usly identified by our laboratory. This nonsense variant leads to a premature te rmination codon at position 4727, which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets our criteria to be classified as p athogenic (http://pcpgm.partners.org/LMM). -

Usher syndrome type 2A Pathogenic:1
Nov 04, 2023
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
37
DANN
Uncertain
0.98
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.36
N
Vest4
0.77
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517989; hg19: chr1-215824097; API