1-215628900-C-T

Position:

chr1-215628900-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The p.Val5145Ile variant in USH2A has been identified in at least 5 individuals with Usher syndrome; however, in 3 individuals no variant on the second allele was identified and in two individuals, no information about the other allele was provided (PMIDs 28041643, 25999674, 20829743, 27353947, 23591405). Additionally, the p.Val5145Ile variant was identified in 2 alleles of 56 retinitis pigmentosa patients, however it is unclear in which one or two patients these alleles were found (PMID 20591486). The filtering allele frequency of the p.Val5145Ile variant in the USH2A gene is 0.7% for European (Finnish) chromosomes by gnomAD (201/25124 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4) .In summary, this variant meets criteria to be classified as benign based primarily on population frequency data and the absence of cases with biallelic variants. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA143401/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 16 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:1B:11

Conservation

PhyloP100: 2.73

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 -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.15433G>A	p.Val5145Ile	missense_variant	71/72	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.15433G>A	p.Val5145Ile	missense_variant	71/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.15505G>A	p.Val5169Ile	missense_variant	72/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00876

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00579

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00314

AC:

789

AN:

251470

Hom.:

AF XY:

0.00320

AC XY:

435

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00771

Gnomad NFE exome

AF:

0.00503

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00435

AC:

6354

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

3107

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00635

Gnomad4 NFE exome

AF:

0.00522

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00365

AC:

555

AN:

152250

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

273

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00876

Gnomad4 NFE

AF:

0.00579

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00500

Hom.:

Bravo

AF:

0.00287

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00315

AC:

382

EpiCase

AF:

0.00442

EpiControl

AF:

0.00409

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	This variant is associated with the following publications: (PMID: 20591486, 20507924, 30245029, 23591405, 26927203, 32707200, 32581362) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2022	Variant summary: USH2A c.15433G>A (p.Val5145Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 251470 control chromosomes in the gnomAD database, including 4 homozygotes. Although reported in the literature, to our knowledge, no penetrant association of c.15433G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2013	Val5145Ile in exon 71 of USH2A: This variant has been identified in one individu al with Usher syndrome or nonsyndromic retinitis pigmentosa and two individuals with nonsyndromic retinitis pigmentosa (van Wijk - unpublished data, McGee 2010, Clark 2010). However, it was not noted if any of these individuals had a second USH2A variant. In addition, this variant has also been identified in one proban d with Fundus albipunctatus who was homozygous for a null mutation in another ge ne (Schatz 2010). It has also been identified by our laboratory in two probands who have other etiologies for their hearing loss. Furthermore, this variant is n ot expected to have clinical significance because it has been identified in 0.6% (48/8600) of European American chromosomes by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs111033269). In summary, this varia nt meets our criteria to be classified as benign. -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Uncertain significance, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Usher syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jan 14, 2019

The p.Val5145Ile variant in USH2A has been identified in at least 5 individuals with Usher syndrome; however, in 3 individuals no variant on the second allele was identified and in two individuals, no information about the other allele was provided (PMIDs 28041643, 25999674, 20829743, 27353947, 23591405). Additionally, the p.Val5145Ile variant was identified in 2 alleles of 56 retinitis pigmentosa patients, however it is unclear in which one or two patients these alleles were found (PMID 20591486). The filtering allele frequency of the p.Val5145Ile variant in the USH2A gene is 0.7% for European (Finnish) chromosomes by gnomAD (201/25124 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4) .In summary, this variant meets criteria to be classified as benign based primarily on population frequency data and the absence of cases with biallelic variants. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Usher syndrome type 2A

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.0022

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.55

REVEL

Benign

0.13

Sift

Benign

0.030

Sift4G

Uncertain

0.038

Polyphen

0.55

Vest4

0.23

MVP

0.58

MPC

0.032

ClinPred

0.017

GERP RS

3.8

Varity_R

0.042

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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