rs746098518

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_206933.4(USH2A):c.15322C>T(p.Arg5108Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,190 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R5108R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.41

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14508101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.15322C>T	p.Arg5108Trp	missense_variant	71/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.15322C>T	p.Arg5108Trp	missense_variant	71/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.15394C>T	p.Arg5132Trp	missense_variant	72/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251096

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135752

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461020

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726832

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg5108Trp va riant in USH2A has not been previously reported in individuals with hearing loss , but has been identified in 1/16490 of South Asian chromosomes and in 1/11562 o f Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs746098518). Arginine (Arg) at position 5108 is not conse rved in mammals or evolutionarily distant species and 2 mammals (Tibetan antelop e and armadillo) carry tryptophan (Trp) at this position, raising the possibilit y that this change may be tolerated. In summary, while the clinical significance of the p.Arg5108Trp variant is uncertain, these data suggest that it is more li kely to be benign. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 28, 2016

- -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.70

M_CAP

Benign

0.070

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-2.2

REVEL

Benign

0.046

Sift

Uncertain

0.015

Sift4G

Uncertain

0.022

Polyphen

0.010

Vest4

0.25

MutPred

0.36

Loss of disorder (P = 0.0018);

MVP

0.69

MPC

0.032

ClinPred

0.55

GERP RS

0.57

Varity_R

0.064

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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