rs4129843

Positions:

chr1-215813880-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.9595A>G(p.Asn3199Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,676 control chromosomes in the GnomAD database, including 2,777 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N3199N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 301 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2476 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.195

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 18 (size 96) in uniprot entity USH2A_HUMAN there are 24 pathogenic changes around while only 7 benign (77%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0016355515).

BP6

Variant 1-215813880-T-C is Benign according to our data. Variant chr1-215813880-T-C is described in ClinVar as [Benign]. Clinvar id is 48631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215813880-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	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9595A>G	p.Asn3199Asp	missense_variant	49/72	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.9595A>G	p.Asn3199Asp	missense_variant	49/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9595A>G	p.Asn3199Asp	missense_variant	49/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0556

AC:

8462

AN:

152058

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0785

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0619

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0560

GnomAD3 exomes

AF:

0.0549

AC:

13784

AN:

250962

Hom.:

604

AF XY:

0.0540

AC XY:

7321

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0814

Gnomad AMR exome

AF:

0.0613

Gnomad ASJ exome

AF:

0.00805

Gnomad EAS exome

AF:

0.169

Gnomad SAS exome

AF:

0.0812

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0438

GnomAD4 exome

AF:

0.0509

AC:

74362

AN:

1461500

Hom.:

2476

Cov.:

AF XY:

0.0511

AC XY:

37145

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0747

Gnomad4 AMR exome

AF:

0.0617

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.0806

Gnomad4 FIN exome

AF:

0.00932

Gnomad4 NFE exome

AF:

0.0464

Gnomad4 OTH exome

AF:

0.0603

GnomAD4 genome

AF:

0.0557

AC:

8477

AN:

152176

Hom.:

301

Cov.:

AF XY:

0.0553

AC XY:

4117

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0787

Gnomad4 AMR

AF:

0.0617

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.0765

Gnomad4 FIN

AF:

0.00651

Gnomad4 NFE

AF:

0.0421

Gnomad4 OTH

AF:

0.0578

Alfa

AF:

0.0462

Hom.:

373

Bravo

AF:

0.0599

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.0781

AC:

344

ESP6500EA

AF:

0.0398

AC:

342

ExAC

AF:

0.0551

AC:

6690

Asia WGS

AF:

0.127

AC:

440

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2008	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 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. -

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	- -

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

0.063

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.8

DANN

Benign

0.19

DEOGEN2

Benign

0.035

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

REVEL

Benign

0.042

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MPC

0.032

ClinPred

0.0043

GERP RS

-0.53

Varity_R

0.042

gMVP

0.13

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