rs4129843

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.9595A>G(p.Asn3199Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,676 control chromosomes in the GnomAD database, including 2,777 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N3199N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 301 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2476 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.195

Publications

30 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 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

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016355515).

BP6

Variant 1-215813880-T-C is Benign according to our data. Variant chr1-215813880-T-C is described in ClinVar as [Benign]. Clinvar id is 48631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.9595A>G	p.Asn3199Asp	missense_variant	Exon 49 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.9595A>G	p.Asn3199Asp	missense_variant	Exon 49 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.9595A>G	p.Asn3199Asp	missense_variant	Exon 49 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0556

AC:

8462

AN:

152058

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0785

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0619

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0560

GnomAD2 exomes

AF:

0.0549

AC:

13784

AN:

250962

AF XY:

0.0540

show subpopulations

Gnomad AFR exome

AF:

0.0814

Gnomad AMR exome

AF:

0.0613

Gnomad ASJ exome

AF:

0.00805

Gnomad EAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0438

GnomAD4 exome

AF:

0.0509

AC:

74362

AN:

1461500

Hom.:

2476

Cov.:

AF XY:

0.0511

AC XY:

37145

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0747

AC:

2501

AN:

33460

American (AMR)

AF:

0.0617

AC:

2761

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00831

AC:

217

AN:

26114

East Asian (EAS)

AF:

0.151

AC:

5982

AN:

39678

South Asian (SAS)

AF:

0.0806

AC:

6950

AN:

86256

European-Finnish (FIN)

AF:

0.00932

AC:

498

AN:

53408

Middle Eastern (MID)

AF:

0.0359

AC:

207

AN:

5764

European-Non Finnish (NFE)

AF:

0.0464

AC:

51607

AN:

1111720

Other (OTH)

AF:

0.0603

AC:

3639

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3900

7800

11700

15600

19500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0557

AC:

8477

AN:

152176

Hom.:

301

Cov.:

AF XY:

0.0553

AC XY:

4117

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0787

AC:

3268

AN:

41514

American (AMR)

AF:

0.0617

AC:

942

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.151

AC:

785

AN:

5182

South Asian (SAS)

AF:

0.0765

AC:

369

AN:

4822

European-Finnish (FIN)

AF:

0.00651

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0421

AC:

2862

AN:

68004

Other (OTH)

AF:

0.0578

AC:

122

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

408

815

1223

1630

2038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0473

Hom.:

741

Bravo

AF:

0.0599

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.0781

AC:

344

ESP6500EA

AF:

0.0398

AC:

342

ExAC

AF:

0.0551

AC:

6690

Asia WGS

AF:

0.127

AC:

440

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 18, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.8

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.035

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.8

PhyloP100

0.20

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

REVEL

Benign

0.042

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MPC

0.032

ClinPred

0.0043

GERP RS

-0.53

Varity_R

0.042

gMVP

0.13

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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rs4129843

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