rs111033524

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (≥0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143472/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 4 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:3U:3B:11

Conservation

PhyloP100: 4.83

Publications

7 publications found

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:

USH2A-AS1 (HGNC:40606): (USH2A antisense RNA 1)

USH2A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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 link	c.3902G>T	p.Gly1301Val	missense_variant	Exon 18 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.3902G>T	p.Gly1301Val	missense_variant	Exon 18 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000833

AC:

209

AN:

250898

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000419

AC:

613

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

428

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00511

AC:

441

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000110

AC:

122

AN:

1111948

Other (OTH)

AF:

0.000580

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000263

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00580

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:3Uncertain:3Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: BP4 -

Jan 17, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jun 22, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The USH2A c.3902G>T; p.Gly1301Val variant (rs111033524) is reported in the medical literature in individuals with Usher syndrome and retinitis pigmentosa, however, one of these individuals also carried an alternate molecular explanation for disease (Bonnet 2011, Pierrache 2016). The variant is reported with discrepant classifications in the ClinVar database (Variation ID: 48509) and in the Genome Aggregation Database in 0.6% (184/30778 alleles) of the South Asian population. The glycine at this codon is moderately conserved but computational analyses (SIFT:Tolerated, PolyPhen-2: Probably Damaging) predict conflicting effects of this variant on protein structure/function. Although there is information indicating this variant may not be pathogenic, there is insufficient evidence to classify the variant with certainty. Pathogenic USH2A variants are causative for autosomal recessive Usher syndrome (MIM: 276901) and retintitis pigmentosa (MIM: 613809). References: Bonnet C et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis. 2011 May 11;6:21. Pierrache LH et al. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2016 May;123(5):1151-60. -

Usher syndrome type 2A

Uncertain:1Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Usher syndrome

Pathogenic:1Benign:1

Dec 31, 2022

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

Mar 20, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (>=0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024). -

Retinitis pigmentosa 39

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A c.3902G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: BP5, BA1, PP3. Based on this evidence we have classified this variant as Benign. -

Usher syndrome type 1

Pathogenic:1

May 19, 2016

GeneReviews

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

not specified

Benign:1

Apr 22, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

USH2A-related disorder

Benign:1

Sep 23, 2022

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

Uncertain

0.39

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

4.8

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.99

D;D

Vest4

0.92

MVP

0.96

MPC

0.19

ClinPred

0.11

GERP RS

4.9

Varity_R

0.50

gMVP

0.78

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over