rs142381713

Positions:

chr1-215728169-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

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 Likely 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain Fibronectin type-III 25 (size 103) in uniprot entity USH2A_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11927C>T	p.Thr3976Met	missense_variant	61/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11927C>T	p.Thr3976Met	missense_variant	61/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11927C>T	p.Thr3976Met	missense_variant	61/73			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

GnomAD3 exomes

AF:

0.000589

AC:

148

AN:

251316

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135822

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000493

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000969

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

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 14, 2024	BS1_supporting, PM3_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 28181551, 17405132, 25910913, 20052763, 30245029, 32579692, 33576794) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	USH2A: PM2, BP4 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2016	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). -

Usher syndrome type 2A

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2023

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over