1-215798994-C-T

Position:

chr1-215798994-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_206933.4(USH2A):c.9871G>A(p.Gly3291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.807

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9871G>A	p.Gly3291Ser	missense_variant	50/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9871G>A	p.Gly3291Ser	missense_variant	50/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9871G>A	p.Gly3291Ser	missense_variant	50/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251216

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000422

AC:

617

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

304

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000525

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000309

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000479

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2024	Reported in the heterozygous state in a patient with Usher syndrome in published literature (PMID: 25333064); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32707200, 25333064) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3291 of the USH2A protein (p.Gly3291Ser). This variant is present in population databases (rs138543813, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25333064). ClinVar contains an entry for this variant (Variation ID: 550545). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 31, 2017

- -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 28, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2018

The p.Gly3291Ser variant has been previously reported in one individual with Ush er syndrome; however the variant reported on the other allele (p.Tyr1992Cys) is classified as benign based on its frequency (Krawitz 2014). The p.Gly3291Ser var iant has been identified in 0.05% (59/126516) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1385438 13). Although this variant has been seen in the general population, its frequen cy is not high enough to rule out a pathogenic role. Computational prediction to ols and conservation analyses suggest that this variant may not impact the prote in, and at least one mammal (shrew) has a Serine at this residue as do other low er species (birds, reptiles, fish). In summary, the clinical significance of the p.Gly3291Ser variant is likely benign. ACMG/AMP Criteria applied: BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.034

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.60

Sift

Benign

0.57

Sift4G

Benign

0.45

Polyphen

0.0060

Vest4

0.71

MVP

0.42

MPC

0.031

ClinPred

0.027

GERP RS

0.40

Varity_R

0.037

gMVP

0.17

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