rs45549044

Positions:

chr1-215671031-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_206933.4(USH2A):c.14074G>A(p.Gly4692Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,614,064 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 39 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.48

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01668179).

BP6

Variant 1-215671031-C-T is Benign according to our data. Variant chr1-215671031-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215671031-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14074G>A	p.Gly4692Arg	missense_variant	64/72	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.14074G>A	p.Gly4692Arg	missense_variant	64/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14074G>A	p.Gly4692Arg	missense_variant	64/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.00432

GnomAD3 exomes

AF:

0.00471

AC:

1182

AN:

250890

Hom.:

AF XY:

0.00494

AC XY:

670

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00359

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00789

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00672

AC:

9817

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

4831

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.00266

Gnomad4 NFE exome

AF:

0.00797

Gnomad4 OTH exome

AF:

0.00588

GnomAD4 genome

AF:

0.00421

AC:

641

AN:

152204

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00745

Gnomad4 OTH

AF:

0.00428

Alfa

AF:

0.00643

Hom.:

Bravo

AF:

0.00404

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00478

AC:

580

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00785

EpiControl

AF:

0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	This variant is associated with the following publications: (PMID: 22004887, 25333064, 25262649, 24944099, 26927203, 19129697, 30245029, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	USH2A: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 25, 2011	Gly4692Ar in Exon 64 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (53/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; rs45549044). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2022	Variant summary: USH2A c.14074G>A (p.Gly4692Arg) results in a non-conservative amino acid change located in the Fibronectin Type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 250890 control chromosomes in the gnomAD database, including 6 homozygotes. Although reported in the literature, to our knowledge, no penetrant association of c.14074G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 06, 2021	- -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

0.19

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.43

Sift

Benign

0.041

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.75

MutPred

0.76

Loss of sheet (P = 0.0357);

MVP

0.87

MPC

0.23

ClinPred

0.019

GERP RS

4.2

Varity_R

0.24

gMVP

0.65

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