rs41302239

Positions:

chr1-216070292-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_206933.4(USH2A):c.5858C>G(p.Ala1953Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000763 in 1,613,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1953A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 3 hom. )

Consequence

USH2A
NM_206933.4 missense, splice_region

Scores

Splicing: ADA: 0.9693

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:15B:5

Conservation

PhyloP100: 4.27

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.

PM1

In a domain Fibronectin type-III 5 (size 86) in uniprot entity USH2A_HUMAN there are 20 pathogenic changes around while only 4 benign (83%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.06280768).

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.5858C>G	p.Ala1953Gly	missense_variant, splice_region_variant	30/72	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.5858C>G	p.Ala1953Gly	missense_variant, splice_region_variant	30/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.5858C>G	p.Ala1953Gly	missense_variant, splice_region_variant	30/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000844

AC:

212

AN:

251114

Hom.:

AF XY:

0.000899

AC XY:

122

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000758

AC:

1108

AN:

1461564

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

578

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000740

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152286

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000993

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000791

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:15Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	This variant is associated with the following publications: (PMID: 24944099, 27145477, 26868535, 28981474, 28041643, 20507924, 33576794) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1953 of the USH2A protein (p.Ala1953Gly). This variant is present in population databases (rs41302239, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa, retinal dystrophy, and Usher syndrome (PMID: 28041643, 28981474, 29142287). ClinVar contains an entry for this variant (Variation ID: 48546). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Usher syndrome type 2A

Pathogenic:1Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 28, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 31, 2019	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Aug 20, 2024	The p.(Ala1953Gly) is a known recessive variant based on PMID: 20507924. It was detected in an hearing impaired individual with a sloping audiogram, normal-to-profound HL. -

Retinal dystrophy

Uncertain:2

Uncertain significance, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Uncertain significance, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: USH2A c.5858C>G (p.Ala1953Gly) results in a non-conservative amino acid change in 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 0.00084 in 251114 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00084 vs 0.011), allowing no conclusion about variant significance. c.5858C>G has been reported in the literature as a heterozygous genotype in combination with other heterozygous variants in the USH2A gene without phase clearly specified in probands with Retinitis Pigmentosa (RP), Retinal Dystrophies (RD), Pericentral Scotoma, and a reported diagnosis of Usher syndrome (example, Chebil_2016, Comander_2017, Carss_2017, Eandi_2017, Colombo_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=10). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2019	The p.Ala1953Gly variant in USH2A has been identified in several individuals with hearing loss, retinitis pigmentosa, and Usher syndrome but has been identified in 0.1% (144/128948) of European chromosomes (http://gnomad.broadinstitute.org). This frequency suggests that the variant may not be pathogenic. Consistent with this, three individuals tested by our laboratory had alternate genetic explanations of their disease, including one individual who was homozygous for the p. Ala1953Gly variant but harbored another homozygous pathogenic USH2A variant. ACMG/AMP criteria applied: BS1_Supporting, BP2, BP5. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

USH2A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.2

REVEL

Benign

0.13

Sift

Benign

0.046

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.26

MVP

0.92

MPC

0.19

ClinPred

0.075

GERP RS

5.6

Varity_R

0.11

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.67

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