rs142381713

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_206933.4(USH2A):c.11927C>T(p.Thr3976Met) variant causes a missense change. The variant allele was found at a frequency of 0.000883 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T3976T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 4.11

Publications

16 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 1-215728169-G-A is Benign according to our data. Variant chr1-215728169-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48385.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11927C>T	p.Thr3976Met	missense_variant	Exon 61 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.11927C>T	p.Thr3976Met	missense_variant	Exon 61 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11927C>T	p.Thr3976Met	missense_variant	Exon 61 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000589

AC:

148

AN:

251316

AF XY:

0.000493

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000923

AC:

1350

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

650

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00113

AC:

1257

AN:

1112008

Other (OTH)

AF:

0.000745

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

162

242

323

404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<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:

0.000493

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41550

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000923

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: PM2, BP4 -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 29, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28181551, 17405132, 25910913, 20052763, 30245029, 32579692, 33576794) -

Aug 14, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1_supporting, PM3_supporting -

Oct 28, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3976 of the USH2A protein (p.Thr3976Met). This variant is present in population databases (rs142381713, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa and/or Usher syndrome (PMID: 17405132, 25910913, 28181551, 33576794). ClinVar contains an entry for this variant (Variation ID: 48385). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1Benign:1

May 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr3976Met in exon 61 of USH2A: This variant is not expected to have clinical significance because it occurs in cis with a pathogenic variant in one individua l with Usher syndrome (Baux 2007, Le Guedard-Mereuze 2010). It has been identifi ed in 0.1% (56/66702) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs142381713). -

May 10, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr3976Met variant (rs142381713) has been observed as part of a complex allele with a different variant, c.3811+3A>T, found in an individual with a clinical diagnosis of Usher syndrome type II (Baux 2007). In addition to this complex allele, the patient in Baux (2007) also carried a clearly pathogenic nonsense variant (p.Leu2301Ter) in trans. Subsequent in vitro analysis of the c.3811+3A>T variant indicated that it almost completely disrupts splicing, leading to skipping of exon 17 (Le Guedard-Mereuze 2010). The c.3811+3A>T variant is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. As a comparison, p.Thr3976Met is listed in the ESP with an allele frequency in European Americans of 0.14% (identified in 12 out of 8,600 chromosomes), and in the ExAC browser with an allele frequency in non-Finnish Europeans of 0.08% (identified in 56 out of 66,702 chromosomes). These observations argue that the c.3811+3A>T is pathogenic, and thus it is likely that the p.Thr3976Met variant is not. However, skipping of exon 17 retains the reading frame of USH2A mRNA, and the c.3811+3A>T variant has not been reported with any other pathogenic alleles. Moreover, the threonine at codon 3976 is highly conserved considering 10 species up to chicken (Alamut software v2.7.1), and computational analyses suggest the p.Thr3976Met variant has a significant effect on USH2A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Therefore, with the uncertainty concerning the pathogenicity of the c.3811+3A>T variant, and the lack of other evidence suggesting the p.Thr3976Met variant is benign, the clinical significance of the p.Thr3976Met variant cannot be determined with certainty. -

Usher syndrome type 2A

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 39

Uncertain:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.8

PhyloP100

4.1

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.30

Sift

Benign

0.056

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.57

MVP

0.97

MPC

0.23

ClinPred

0.14

GERP RS

5.5

Varity_R

0.23

gMVP

0.42

Mutation Taster

=32/68

disease causing

(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