rs112459877

Positions:

chr1-215650659-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: The c.14276G>A (p.Gly4759Glu) variant has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa (PS4/PM3 not met; Partners LMM internal data, PMID 28041643). However, the filtering allele frequency (the lower threshold of the 95% CI of 102/24022) of the p.Gly4759Glu variant in the USH2A gene is 0.425% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA180987/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:5

Conservation

PhyloP100: -0.656

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 Likely_benign. Variant got -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14276G>A	p.Gly4759Glu	missense_variant	65/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.14276G>A	p.Gly4759Glu	missense_variant	65/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14276G>A	p.Gly4759Glu	missense_variant	65/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000259

AC:

AN:

251184

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152184

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00412

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	Observed in a patient with retinitis pigmentosa in published literature (Carss et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28041643) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2022	Variant summary: USH2A c.14276G>A (p.Gly4759Glu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251184 control chromosomes, predominantly at a frequency of 0.0038 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00026 vs 0.011), allowing no conclusion about variant significance. c.14276G>A has been reported in the literature as a non-informative genotype with three other missense variants in the USH2A gene (phase not specified) in at-least one individual of African ethnicity reportedly affected with with Retinitis Pigmentosa (RP) analyzed by whole genome sequencing (WGS) and reported as "Partially Solved" (example, Carrs_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and the ClinGen Hearing Loss Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (VUS, n=4, likely benign, n=2 including the expert panel). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2013	The Gly4759Glu variant in USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.34% (15/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs112459877). -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 10, 2017

- -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 12, 2020

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Usher syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

May 14, 2019

The c.14276G>A (p.Gly4759Glu) variant has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa (PS4/PM3 not met; Partners LMM internal data, PMID 28041643). However, the filtering allele frequency (the lower threshold of the 95% CI of 102/24022) of the p.Gly4759Glu variant in the USH2A gene is 0.425% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). -

USH2A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0010

DANN

Benign

0.13

DEOGEN2

Benign

0.020

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.11

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.70

PrimateAI

Benign

0.20

PROVEAN

Benign

0.70

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.16

MVP

0.55

MPC

0.035

ClinPred

0.015

GERP RS

-12

Varity_R

0.037

gMVP

0.44

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