NM_206933.4:c.14276G>A

Variant names:

• chr1-215650659-C-T
• rs112459877
• NM_206933.4:c.14276G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.14276G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 4759 (p.Gly4759Glu). The filtering allele frequency (the lower threshold of the 95% CI of (295/75006) of this variant is 0.35% for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen Hearing Loss VCEP threshold >0.3% for BS1, and therefore meets this criterion (BS1). It has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa; however, given the allele frequency and lack of a second pathogenic variant in trans, no evidence is met (PS4/PM3 not met; SCV000204243.5, PMID 28041643). In summary, this variant has been classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). 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
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:5
• Conservation: PhyloP100: -0.656
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.14276G>A	p.Gly4759Glu	missense_variant	Exon 65 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.14276G>A	p.Gly4759Glu	missense_variant	Exon 65 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.14276G>A	p.Gly4759Glu	missense_variant	Exon 65 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152066 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251184 AF XY: 0.000140

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 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.: 0 Cov.: 33 AF XY: 0.0000756 AC XY: 55 AN XY: 727244

African (AFR) AF: 0.00370 AC: 124 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152184 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74390

African (AFR) AF: 0.00412 AC: 171 AN: 41528

American (AMR) AF: 0.000262 AC: 4 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.00117

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

not specified Benign:2

May 10, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 10, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Usher syndrome type 2A Uncertain:1

Feb 12, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa Uncertain:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Usher syndrome Benign:1

May 21, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.14276G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 4759 (p.Gly4759Glu). The filtering allele frequency (the lower threshold of the 95% CI of (295/75006) of this variant is 0.35% for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen Hearing Loss VCEP threshold >0.3% for BS1, and therefore meets this criterion (BS1). It has been detected in at least 4 heterozygous individuals with clinical features of hearing loss or retinitis pigmentosa; however, given the allele frequency and lack of a second pathogenic variant in trans, no evidence is met (PS4/PM3 not met; SCV000204243.5, PMID 28041643). In summary, this variant has been classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). -

USH2A-related disorder Benign:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0010
DANN	Benign	0.13
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.70	N
PhyloP100		-0.66
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.55
MPC		0.035
ClinPred		0.015	T
GERP RS		-12
Varity_R		0.037
gMVP		0.44
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs112459877; hg19: chr1-215824001;