1-216421964-C-T

Position:

chr1-216421964-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.373G>A(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,698 control chromosomes in the GnomAD database, including 418,913 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A125A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.73 ( 40885 hom., cov: 32)

Exomes 𝑓: 0.72 ( 378028 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.358

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3263331E-6).

BP6

Variant 1-216421964-C-T is Benign according to our data. Variant chr1-216421964-C-T is described in ClinVar as [Benign]. Clinvar id is 48507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216421964-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.373G>A	p.Ala125Thr	missense_variant	2/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.373G>A	p.Ala125Thr	missense_variant	2/21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.373G>A	p.Ala125Thr	missense_variant	2/72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.373G>A	p.Ala125Thr	missense_variant	2/21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.373G>A	p.Ala125Thr	missense_variant	2/73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111235

AN:

151902

Hom.:

40838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.756

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.832

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.779

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.708

Gnomad OTH

AF:

0.695

GnomAD3 exomes

AF:

0.729

AC:

182834

AN:

250924

Hom.:

66950

AF XY:

0.725

AC XY:

98340

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.757

Gnomad AMR exome

AF:

0.730

Gnomad ASJ exome

AF:

0.658

Gnomad EAS exome

AF:

0.836

Gnomad SAS exome

AF:

0.732

Gnomad FIN exome

AF:

0.774

Gnomad NFE exome

AF:

0.705

Gnomad OTH exome

AF:

0.700

GnomAD4 exome

AF:

0.718

AC:

1049721

AN:

1461678

Hom.:

378028

Cov.:

AF XY:

0.717

AC XY:

521325

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.757

Gnomad4 AMR exome

AF:

0.731

Gnomad4 ASJ exome

AF:

0.654

Gnomad4 EAS exome

AF:

0.845

Gnomad4 SAS exome

AF:

0.728

Gnomad4 FIN exome

AF:

0.768

Gnomad4 NFE exome

AF:

0.711

Gnomad4 OTH exome

AF:

0.715

GnomAD4 genome

AF:

0.732

AC:

111334

AN:

152020

Hom.:

40885

Cov.:

AF XY:

0.737

AC XY:

54765

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.756

Gnomad4 AMR

AF:

0.723

Gnomad4 ASJ

AF:

0.657

Gnomad4 EAS

AF:

0.833

Gnomad4 SAS

AF:

0.760

Gnomad4 FIN

AF:

0.779

Gnomad4 NFE

AF:

0.708

Gnomad4 OTH

AF:

0.697

Alfa

AF:

0.706

Hom.:

97910

Bravo

AF:

0.727

TwinsUK

AF:

0.718

AC:

2661

ALSPAC

AF:

0.710

AC:

2736

ESP6500AA

AF:

0.758

AC:

3339

ESP6500EA

AF:

0.699

AC:

6012

ExAC

AF:

0.729

AC:

88518

Asia WGS

AF:

0.788

AC:

2742

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

Usher syndrome type 2A

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Dec 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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 03, 2025	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.9

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.59

N;N

REVEL

Benign

0.084

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.0030

MPC

0.030

ClinPred

0.0021

GERP RS

-1.4

Varity_R

0.041

gMVP

0.24

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