1-215786825-T-G

Position:

chr1-215786825-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.10232A>C(p.Glu3411Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,422 control chromosomes in the GnomAD database, including 235,006 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3411D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.58 ( 25969 hom., cov: 31)

Exomes 𝑓: 0.53 ( 209037 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.96

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 Benign. Variant got -18 ACMG points.

PM1

In a domain Fibronectin type-III 19 (size 94) in uniprot entity USH2A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=3.6495892E-6).

BP6

Variant 1-215786825-T-G is Benign according to our data. Variant chr1-215786825-T-G is described in ClinVar as [Benign]. Clinvar id is 48344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215786825-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.10232A>C	p.Glu3411Ala	missense_variant	52/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.10232A>C	p.Glu3411Ala	missense_variant	52/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.10232A>C	p.Glu3411Ala	missense_variant	52/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

88021

AN:

151814

Hom.:

25934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.683

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.559

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.525

Gnomad OTH

AF:

0.586

GnomAD3 exomes

AF:

0.548

AC:

137379

AN:

250598

Hom.:

38053

AF XY:

0.543

AC XY:

73614

AN XY:

135468

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.575

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.634

Gnomad SAS exome

AF:

0.495

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.521

Gnomad OTH exome

AF:

0.547

GnomAD4 exome

AF:

0.533

AC:

779652

AN:

1461490

Hom.:

209037

Cov.:

AF XY:

0.532

AC XY:

387031

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.694

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.533

Gnomad4 EAS exome

AF:

0.632

Gnomad4 SAS exome

AF:

0.496

Gnomad4 FIN exome

AF:

0.552

Gnomad4 NFE exome

AF:

0.525

Gnomad4 OTH exome

AF:

0.543

GnomAD4 genome

AF:

0.580

AC:

88111

AN:

151932

Hom.:

25969

Cov.:

AF XY:

0.581

AC XY:

43104

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.684

Gnomad4 AMR

AF:

0.579

Gnomad4 ASJ

AF:

0.527

Gnomad4 EAS

AF:

0.633

Gnomad4 SAS

AF:

0.493

Gnomad4 FIN

AF:

0.559

Gnomad4 NFE

AF:

0.525

Gnomad4 OTH

AF:

0.585

Alfa

AF:

0.539

Hom.:

44504

Bravo

AF:

0.586

TwinsUK

AF:

0.533

AC:

1977

ALSPAC

AF:

0.526

AC:

2029

ESP6500AA

AF:

0.672

AC:

2959

ESP6500EA

AF:

0.519

AC:

4462

ExAC

AF:

0.547

AC:

66335

Asia WGS

AF:

0.558

AC:

1939

AN:

3476

EpiCase

AF:

0.526

EpiControl

AF:

0.534

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Caucasian data = 3655/7020 (ESP data) -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.14

DEOGEN2

Benign

0.020

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0000036

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.086

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.076

MPC

0.031

ClinPred

0.0064

GERP RS

4.9

Varity_R

0.033

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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