rs397517925

Positions:

chr17-74919463-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_173477.5(USH1G):c.1373A>T(p.Asp458Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,606,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 17-74919463-T-A is Pathogenic according to our data. Variant chr17-74919463-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74919463-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
USH1G	NM_173477.5 linkuse as main transcript	c.1373A>T	p.Asp458Val	missense_variant	2/3	ENST00000614341.5
USH1G	NM_001282489.3 linkuse as main transcript	c.1064A>T	p.Asp355Val	missense_variant	2/3
USH1G	XM_011524296.2 linkuse as main transcript	c.1064A>T	p.Asp355Val	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5 linkuse as main transcript	c.1373A>T	p.Asp458Val	missense_variant	2/3	1	NM_173477.5	P1
USH1G	ENST00000579243.1 linkuse as main transcript	c.*972A>T		3_prime_UTR_variant, NMD_transcript_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151656

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240980

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132704

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000930

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1455268

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723548

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74032

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:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1G

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jun 10, 2024	Pathogenic by Deafness Variation Database based on PMID: 16283141 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Apr 26, 2019	This variant was identified in an homozygous state in a young female patient profound hearing loss. It was inherited from both parents (asymptomatic heterozygous carriers). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 458 of the USH1G protein (p.Asp458Val). This variant is present in population databases (rs397517925, gnomAD 0.002%). This missense change has been observed in individual(s) with atypical Usher syndrome (PMID: 16283141, 28944237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48127). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects USH1G function (PMID: 20142502). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 03, 2011

The Asp458Val variant in USH1G has been identified as a homozygous variant in tw o Turkish probands with moderate to severe and profound hearing loss and was als o detected in 1/498 Turkish control chromosomes (Kalay 2005). In addition, the v ariant was also homozygous in four affected relatives of these probands, and 18 unaffected relatives were either heterozygous for the variant or were wild-type. The affected individuals in these two families were not reported to have vestib ular dysfunction, and did not report visual problems; however funduscopy suggest ed mild retinitis pigmentosa. Electroretinograms were not performed in affected individuals (Kalay 2005). In summary, this variant is likely to be pathogenic, t hough additional studies are required to fully establish its clinical significan ce. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.70

Loss of solvent accessibility (P = 0.0371);

MVP

0.62

ClinPred

0.98

GERP RS

4.5

Varity_R

0.95

gMVP

0.85

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