NM_206933.4:c.12874A>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3_StrongPP3PP1

This summary comes from the ClinGen Evidence Repository: The c.12874A>G variant in USH2A is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 4292 (p.Asn4292Asp). The highest population frequency in gnomAD v4.1.0 is 0.02% (20/86258 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.707, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been identified in at least 6 individuals with apparently isolated retinal dystrophy. One individual was homozygous, one was heterozygous for a second variant of uncertain significance, three had a second pathogenic variant with phase unknown, and one harbored a second pathogenic variant confirmed in trans (2 points, PM3_Strong, PMID:28041643, 25133751, 37322672, Invitae Internal evidence SCV001403886.5, Blueprint Genetics internal evidence SCV001240918.1). The variant has been reported to segregate with retinal dystrophy in 1 affected family member from 1 family (PP1; PMID:25133751). Of note, hearing loss was not reported in any of these individuals, indicating that this variant is likely causative for isolated retinal dystrophy and not Usher syndrome. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_Strong, PP1. (Hearing loss VCEP specifications version 2; 05.15.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143304/MONDO:0019501/005

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:3

Conservation

PhyloP100: 4.85

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_pathogenic. Variant got 6 ACMG points.

PM3

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

PP1

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

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12874A>G	p.Asn4292Asp	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.12874A>G	p.Asn4292Asp	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.12874A>G	p.Asn4292Asp	missense_variant	Exon 63 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251114

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:2

Nov 28, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.12874A>G variant in USH2A is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 4292 (p.Asn4292Asp). The highest population frequency in gnomAD v4.1.0 is 0.02% (20/86258 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.707, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been identified in at least 6 individuals with apparently isolated retinal dystrophy. One individual was homozygous, one was heterozygous for a second variant of uncertain significance, three had a second pathogenic variant with phase unknown, and one harbored a second pathogenic variant confirmed in trans (2 points, PM3_Strong, PMID: 28041643, 25133751, 37322672, Invitae Internal evidence SCV001403886.5, Blueprint Genetics internal evidence SCV001240918.1). The variant has been reported to segregate with retinal dystrophy in 1 affected family member from 1 family (PP1; PMID: 25133751). Of note, hearing loss was not reported in any of these individuals, indicating that this variant is likely causative for isolated retinal dystrophy and not Usher syndrome. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_Strong, PP1. (Hearing loss VCEP specifications version 2; 05.15.2024). -

not provided

Pathogenic:1Uncertain:1

Oct 08, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed phase unknown with a second USH2A variant in a patient with retinitis pigmentosa in published literature (Carss et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (SCV001428433.1; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28041643, 25133751, 32637036, 32581362) -

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 4292 of the USH2A protein (p.Asn4292Asp). This variant is present in population databases (rs397517984, gnomAD 0.02%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25133751, 28041643; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48409). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Jun 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39

Pathogenic:1

Jan 23, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified

Uncertain:1

Jan 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asn4292Asp variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong supp ort for or against pathogenicity. -

Usher syndrome type 2A

Uncertain:1

Nov 16, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_206933.2(USH2A):c.12874A>G(N4292D) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. N4292D has been observed in cases with relevant disease (PMID: 25133751, 28041643). Functional assessments of this variant are not available in the literature. N4292D has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.12874A>G(N4292D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.075

MutationAssessor

Pathogenic

3.3

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.71

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.81

MutPred

0.67

Loss of glycosylation at P4287 (P = 0.1314);

MVP

0.94

MPC

0.24

ClinPred

0.95

GERP RS

4.1

Varity_R

0.36

gMVP

0.77

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