1-215838019-T-C

Position:

chr1-215838019-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.9343A>G(p.Thr3115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 1,613,802 control chromosomes in the GnomAD database, including 2,531 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 (★★).

Frequency

Genomes: 𝑓 0.036 ( 168 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2363 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0680

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.001318723).

BP6

Variant 1-215838019-T-C is Benign according to our data. Variant chr1-215838019-T-C is described in ClinVar as [Benign]. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9343A>G	p.Thr3115Ala	missense_variant	47/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9343A>G	p.Thr3115Ala	missense_variant	47/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9343A>G	p.Thr3115Ala	missense_variant	47/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0361

AC:

5492

AN:

152178

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0540

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0769

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0439

GnomAD3 exomes

AF:

0.0497

AC:

12498

AN:

251308

Hom.:

550

AF XY:

0.0504

AC XY:

6839

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0580

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.169

Gnomad SAS exome

AF:

0.0814

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0490

AC:

71657

AN:

1461506

Hom.:

2363

Cov.:

AF XY:

0.0496

AC XY:

36036

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00812

Gnomad4 AMR exome

AF:

0.0579

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.0805

Gnomad4 FIN exome

AF:

0.00927

Gnomad4 NFE exome

AF:

0.0464

Gnomad4 OTH exome

AF:

0.0553

GnomAD4 genome

AF:

0.0360

AC:

5486

AN:

152296

Hom.:

168

Cov.:

AF XY:

0.0364

AC XY:

2714

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.0538

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.0768

Gnomad4 FIN

AF:

0.00659

Gnomad4 NFE

AF:

0.0421

Gnomad4 OTH

AF:

0.0449

Alfa

AF:

0.0423

Hom.:

294

Bravo

AF:

0.0371

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0398

AC:

342

ExAC

AF:

0.0487

AC:

5917

Asia WGS

AF:

0.112

AC:

387

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2014	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	Jun 24, 2009	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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

0.065

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.7

DANN

Benign

0.44

DEOGEN2

Benign

0.031

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.48

REVEL

Benign

0.14

Sift

Benign

0.79

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.053

MPC

0.030

ClinPred

0.0032

GERP RS

-5.6

Varity_R

0.034

gMVP

0.20

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