Variant rs148674752 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_206933.4(USH2A):c.14191G>T(p.Gly4731Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4731R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.14

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14191G>T	p.Gly4731Trp	missense_variant	65/72	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.14191G>T	p.Gly4731Trp	missense_variant	65/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14191G>T	p.Gly4731Trp	missense_variant	65/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251370

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with USH2A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 4731 of the USH2A protein (p.Gly4731Trp). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.37

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.42

MutPred

0.45

Loss of disorder (P = 0.0311);

MVP

0.93

MPC

0.14

ClinPred

0.95

GERP RS

4.8

Varity_R

0.28

gMVP

0.74

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