1-215640723-G-A

Position:

chr1-215640723-G-A

Variant summary

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

The NM_206933.4(USH2A):c.14803C>T(p.Arg4935Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,098 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

USH2A
NM_206933.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.70

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]

USH2A links:

Genome browser will be placed here

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 1-215640723-G-A is Pathogenic according to our data. Variant chr1-215640723-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 177760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215640723-G-A is described in Lovd as [Pathogenic]. Variant chr1-215640723-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-215640723-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14803C>T	p.Arg4935Ter	stop_gained	68/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.14803C>T	p.Arg4935Ter	stop_gained	68/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14803C>T	p.Arg4935Ter	stop_gained	68/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251364

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151226

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73782

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change creates a premature translational stop signal (p.Arg4935*) 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 present in population databases (rs146733615, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 17405132, 29142287). ClinVar contains an entry for this variant (Variation ID: 177760). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2016

The p.Arg4935X variant in USH2A has been previously reported in more than nine i ndividuals with either Usher syndrome type II or retinitis pigmentosa (Baux 2007 , Ebermann 2009, Sandberg 2008, McGee 2010, Besnard 2013, LMM data). This varia nt has been also identified in 2/66718 European chromosomes by the Exome Aggrega tion Consortium (http://exac.broadinstitute.org/; dpSNP rs146733615). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency of a recessive disorder. This nonsens e variant leads to a premature termination codon at position 4935, which is pred icted to lead to a truncated or absent protein. In summary, this variant meets c riteria to be classified as pathogenic for autosomal recessive Usher syndrome. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 15, 2018

- -

USH2A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The USH2A c.14803C>T variant is predicted to result in premature protein termination (p.Arg4935*). This variant has been reported many times in individuals with Usher syndrome (see for examples: Baux et al. 2007. PubMed ID: 17405132; Supplemental table, Pierrache et al. 2016. PubMed ID: 26927203; Table S2, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in USH2A are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.97

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A

Vest4

0.69

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over