chr1-215817137-C-T

Position:

chr1-215817137-C-T

Variant summary

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

The ENST00000307340.8(USH2A):c.9430G>A(p.Asp3144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,664 control chromosomes in the GnomAD database, including 773 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 (★★).

Frequency

Genomes: 𝑓 0.034 ( 96 hom., cov: 32)

Exomes 𝑓: 0.028 ( 677 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.34

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 0 benign, 7 uncertain in ENST00000307340.8

BP4

Computational evidence support a benign effect (MetaRNN=0.0061059594).

BP6

Variant 1-215817137-C-T is Benign according to our data. Variant chr1-215817137-C-T is described in ClinVar as [Benign]. Clinvar id is 48627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215817137-C-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 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.9430G>A	p.Asp3144Asn	missense_variant	48/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9430G>A	p.Asp3144Asn	missense_variant	48/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9430G>A	p.Asp3144Asn	missense_variant	48/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5133

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0499

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.0398

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0258

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0446

GnomAD3 exomes

AF:

0.0260

AC:

6499

AN:

250212

Hom.:

AF XY:

0.0257

AC XY:

3469

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.0510

Gnomad AMR exome

AF:

0.0248

Gnomad ASJ exome

AF:

0.0383

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00448

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0284

AC:

41486

AN:

1460694

Hom.:

677

Cov.:

AF XY:

0.0279

AC XY:

20263

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.0527

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0398

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00348

Gnomad4 FIN exome

AF:

0.0274

Gnomad4 NFE exome

AF:

0.0303

Gnomad4 OTH exome

AF:

0.0315

GnomAD4 genome

AF:

0.0339

AC:

5146

AN:

151970

Hom.:

Cov.:

AF XY:

0.0336

AC XY:

2494

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.0501

Gnomad4 AMR

AF:

0.0359

Gnomad4 ASJ

AF:

0.0398

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0258

Gnomad4 NFE

AF:

0.0287

Gnomad4 OTH

AF:

0.0446

Alfa

AF:

0.0301

Hom.:

128

Bravo

AF:

0.0376

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.0522

AC:

230

ESP6500EA

AF:

0.0301

AC:

259

ExAC

AF:

0.0265

AC:

3212

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0297

EpiControl

AF:

0.0352

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.59

D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Uncertain

0.016

Sift4G

Uncertain

0.022

Polyphen

0.022

Vest4

0.054

MPC

0.033

ClinPred

0.017

GERP RS

4.3

Varity_R

0.15

gMVP

0.35

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