rs11120616

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.11504C>T(p.Thr3835Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,605,504 control chromosomes in the GnomAD database, including 37,953 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3835T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 2981 hom., cov: 28)

Exomes 𝑓: 0.21 ( 34972 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.36

Publications

36 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=0.002463013).

BP6

Variant 1-215743221-G-A is Benign according to our data. Variant chr1-215743221-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11504C>T	p.Thr3835Ile	missense_variant	Exon 59 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.11504C>T	p.Thr3835Ile	missense_variant	Exon 59 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11504C>T	p.Thr3835Ile	missense_variant	Exon 59 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28587

AN:

149672

Hom.:

2984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.191

AC:

48017

AN:

250788

AF XY:

0.191

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.0927

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.214

AC:

311628

AN:

1455712

Hom.:

34972

Cov.:

AF XY:

0.211

AC XY:

152604

AN XY:

724170

show subpopulations

African (AFR)

AF:

0.140

AC:

4682

AN:

33338

American (AMR)

AF:

0.199

AC:

8862

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

5130

AN:

25916

East Asian (EAS)

AF:

0.134

AC:

5283

AN:

39456

South Asian (SAS)

AF:

0.0989

AC:

8510

AN:

86052

European-Finnish (FIN)

AF:

0.239

AC:

12656

AN:

52966

Middle Eastern (MID)

AF:

0.205

AC:

1177

AN:

5736

European-Non Finnish (NFE)

AF:

0.228

AC:

253105

AN:

1107704

Other (OTH)

AF:

0.204

AC:

12223

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

12600

25200

37801

50401

63001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8568

17136

25704

34272

42840

<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:

0.191

AC:

28585

AN:

149792

Hom.:

2981

Cov.:

AF XY:

0.188

AC XY:

13706

AN XY:

72990

show subpopulations

African (AFR)

AF:

0.137

AC:

5590

AN:

40874

American (AMR)

AF:

0.207

AC:

3083

AN:

14916

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

676

AN:

3450

East Asian (EAS)

AF:

0.104

AC:

528

AN:

5082

South Asian (SAS)

AF:

0.0768

AC:

364

AN:

4740

European-Finnish (FIN)

AF:

0.223

AC:

2271

AN:

10190

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.228

AC:

15370

AN:

67280

Other (OTH)

AF:

0.212

AC:

438

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

994

1988

2981

3975

4969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.214

Hom.:

15802

Bravo

AF:

0.191

ESP6500AA

AF:

0.143

AC:

628

ESP6500EA

AF:

0.233

AC:

2005

ExAC

AF:

0.192

AC:

23297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 16, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2013

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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;C3151138:Retinitis pigmentosa 39

Benign:1

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

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

0.088

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

Eigen

Benign

-0.11

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

REVEL

Benign

0.10

Sift

Benign

0.18

Sift4G

Benign

0.076

Polyphen

0.055

Vest4

0.031

MPC

0.039

ClinPred

0.012

GERP RS

4.9

Varity_R

0.11

gMVP

0.26

Mutation Taster

=98/2

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