1-215674202-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_206933.4(USH2A):c.13709G>A(p.Arg4570His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,072 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R4570P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 11 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.773

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-215674203-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.009426177).

BP6

Variant 1-215674202-C-T is Benign according to our data. Variant chr1-215674202-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48422.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1}. Variant chr1-215674202-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00122 (1780/1461856) while in subpopulation MID AF= 0.017 (98/5768). AF 95% confidence interval is 0.0143. There are 11 homozygotes in gnomad4_exome. There are 933 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.13709G>A	p.Arg4570His	missense_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.13709G>A	p.Arg4570His	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.13709G>A	p.Arg4570His	missense_variant	Exon 63 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

258

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00518

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00186

AC:

467

AN:

251312

Hom.:

AF XY:

0.00201

AC XY:

273

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000959

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00122

AC:

1780

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

933

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00323

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.0187

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00159

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000602

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.00169

AC:

258

AN:

152216

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00517

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00160

AC:

194

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 29, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg4570His in exon 63 of USH2A: This variant has been identified in a proband wi th Usher syndrome type 2 and in a proband with nonsyndromic retinitis pigmentosa (McGee 2010). However, in both cases the variant was in heterozygous form witho ut a variant on the second allele and this variant was classified as benign (McG ee 2010). This is consistent with our computational analyses (PolyPhen, SIFT, Al ignGVGD) which do not suggest a high likelihood of impact to the protein. In add ition, this variant has also been reported in dbSNP with a frequency of 0.6% (43 /6927) control chromosomes (rs730254). In summary, this evidence suggests the va riant is benign. -

Feb 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH2A: BP4, BS1 -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2A

Benign:2

Jan 13, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39

Uncertain:1

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The USH2A c.13709G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: BP4. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.0

REVEL

Benign

0.10

Sift

Benign

0.14

Sift4G

Benign

0.11

Polyphen

0.45

Vest4

0.10

MVP

0.92

MPC

0.038

ClinPred

0.016

GERP RS

3.6

Varity_R

0.077

gMVP

0.39

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