NM_206933.4:c.9343A>G

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.9343A>G(p.Thr3115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 1,613,802 control chromosomes in the GnomAD database, including 2,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 168 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2363 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0680

Publications

28 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=0.001318723).

BP6

Variant 1-215838019-T-C is Benign according to our data. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.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.9343A>G	p.Thr3115Ala	missense_variant	Exon 47 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.9343A>G	p.Thr3115Ala	missense_variant	Exon 47 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.9343A>G	p.Thr3115Ala	missense_variant	Exon 47 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0361

AC:

5492

AN:

152178

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0540

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0769

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0439

GnomAD2 exomes

AF:

0.0497

AC:

12498

AN:

251308

AF XY:

0.0504

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0580

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0490

AC:

71657

AN:

1461506

Hom.:

2363

Cov.:

AF XY:

0.0496

AC XY:

36036

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.00812

AC:

272

AN:

33478

American (AMR)

AF:

0.0579

AC:

2591

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00831

AC:

217

AN:

26126

East Asian (EAS)

AF:

0.151

AC:

5985

AN:

39670

South Asian (SAS)

AF:

0.0805

AC:

6939

AN:

86244

European-Finnish (FIN)

AF:

0.00927

AC:

495

AN:

53418

Middle Eastern (MID)

AF:

0.0317

AC:

183

AN:

5768

European-Non Finnish (NFE)

AF:

0.0464

AC:

51635

AN:

1111700

Other (OTH)

AF:

0.0553

AC:

3340

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

3387

6775

10162

13550

16937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2110

4220

6330

8440

10550

<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:

0.0360

AC:

5486

AN:

152296

Hom.:

168

Cov.:

AF XY:

0.0364

AC XY:

2714

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0101

AC:

420

AN:

41576

American (AMR)

AF:

0.0538

AC:

822

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.152

AC:

787

AN:

5180

South Asian (SAS)

AF:

0.0768

AC:

371

AN:

4832

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0421

AC:

2862

AN:

68022

Other (OTH)

AF:

0.0449

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

272

543

815

1086

1358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0419

Hom.:

587

Bravo

AF:

0.0371

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0398

AC:

342

ExAC

AF:

0.0487

AC:

5917

Asia WGS

AF:

0.112

AC:

387

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2014

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:2Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

0.065

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.7

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.031

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

PhyloP100

0.068

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.48

REVEL

Benign

0.14

Sift

Benign

0.79

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.053

MPC

0.030

ClinPred

0.0032

GERP RS

-5.6

Varity_R

0.034

gMVP

0.20

Mutation Taster

=88/12

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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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