chr1-215844349-A-G

Position:

chr1-215844349-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_206933.4(USH2A):c.9203T>C(p.Val3068Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3068M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.494

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020991892).

BP6

Variant 1-215844349-A-G is Benign according to our data. Variant chr1-215844349-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48614.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9203T>C	p.Val3068Ala	missense_variant	46/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9203T>C	p.Val3068Ala	missense_variant	46/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9203T>C	p.Val3068Ala	missense_variant	46/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000411

AC:

103

AN:

250692

Hom.:

AF XY:

0.000391

AC XY:

AN XY:

135468

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000579

AC:

846

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000568

AC XY:

413

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.000694

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000473

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000718

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	Reported in an individual with hearing loss who also harbored a nonsense variant on the same USH2A allele (in cis), however, this individual did not have an additional disease-causing variant on the opposite allele (in trans) (Tang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25991456, 32707200, 32483926) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2016	- -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 01, 2021

NM_206933.2(USH2A):c.9203T>C(V3068A) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. V3068A has been observed in cases with relevant disease (PMID: 25991456). Functional assessments of this variant are not available in the literature. V3068A has been observed in population frequency databases (gnomAD: NFE 0.07%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.9203T>C(V3068A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2017

p.Val3068Ala in exon 46 of USH2A: This variant is not expected to have clinical significance because of a lack of conservation across species including mammals. Of note, rat, mouse and opossum have an alanine at this position despite high n earby amino acid conservation. It has been identified in 85/126144 of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs146445078). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.026

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.50

M_CAP

Benign

0.034

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.090

REVEL

Benign

0.066

Sift

Benign

0.83

Sift4G

Benign

0.93

Polyphen

0.0010

Vest4

0.26

MVP

0.69

MPC

0.034

ClinPred

0.0061

GERP RS

3.7

Varity_R

0.030

gMVP

0.22

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