1-215741484-T-C

Position:

chr1-215741484-T-C

Variant summary

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

The NM_206933.4(USH2A):c.11602A>G(p.Met3868Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,586 control chromosomes in the GnomAD database, including 38,998 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3868L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 3492 hom., cov: 31)

Exomes 𝑓: 0.22 ( 35506 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.26

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 24 (size 97) in uniprot entity USH2A_HUMAN there are 25 pathogenic changes around while only 7 benign (78%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0016642809).

BP6

Variant 1-215741484-T-C is Benign according to our data. Variant chr1-215741484-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215741484-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 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.11602A>G	p.Met3868Val	missense_variant	60/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.11602A>G	p.Met3868Val	missense_variant	60/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.11602A>G	p.Met3868Val	missense_variant	60/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31814

AN:

151834

Hom.:

3494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.190

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0813

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.235

GnomAD3 exomes

AF:

0.196

AC:

49194

AN:

251298

Hom.:

5194

AF XY:

0.194

AC XY:

26354

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.0936

Gnomad SAS exome

AF:

0.0984

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.217

AC:

317029

AN:

1461636

Hom.:

35506

Cov.:

AF XY:

0.213

AC XY:

155180

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.192

Gnomad4 AMR exome

AF:

0.203

Gnomad4 ASJ exome

AF:

0.201

Gnomad4 EAS exome

AF:

0.136

Gnomad4 SAS exome

AF:

0.100

Gnomad4 FIN exome

AF:

0.241

Gnomad4 NFE exome

AF:

0.230

Gnomad4 OTH exome

AF:

0.209

GnomAD4 genome

AF:

0.209

AC:

31826

AN:

151950

Hom.:

3492

Cov.:

AF XY:

0.207

AC XY:

15354

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.190

Gnomad4 AMR

AF:

0.218

Gnomad4 ASJ

AF:

0.197

Gnomad4 EAS

AF:

0.107

Gnomad4 SAS

AF:

0.0817

Gnomad4 FIN

AF:

0.233

Gnomad4 NFE

AF:

0.232

Gnomad4 OTH

AF:

0.232

Alfa

AF:

0.212

Hom.:

4815

Bravo

AF:

0.207

TwinsUK

AF:

0.231

AC:

855

ALSPAC

AF:

0.236

AC:

911

ESP6500AA

AF:

0.190

AC:

835

ESP6500EA

AF:

0.233

AC:

2006

ExAC

AF:

0.196

AC:

23802

Asia WGS

AF:

0.108

AC:

376

AN:

3478

EpiCase

AF:

0.230

EpiControl

AF:

0.230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2013	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2014	- -

not provided

Benign:2

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:2

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

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

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

0.060

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0020

DANN

Benign

0.52

DEOGEN2

Benign

0.037

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.20

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.33

REVEL

Benign

0.017

Sift

Benign

1.0

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.028

MPC

0.030

ClinPred

0.014

GERP RS

-9.7

Varity_R

0.050

gMVP

0.30

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