17-74920335-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_173477.5(USH1G):c.501C>G(p.Arg167Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,610,074 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 11 hom. )

Consequence

USH1G
NM_173477.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.875

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 17-74920335-G-C is Benign according to our data. Variant chr17-74920335-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48132.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr17-74920335-G-C is described in Lovd as [Likely_benign]. Variant chr17-74920335-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.875 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00185 (282/152372) while in subpopulation NFE AF= 0.0027 (184/68040). AF 95% confidence interval is 0.00238. There are 1 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5 link	c.501C>G	p.Arg167Arg	synonymous_variant	Exon 2 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 link	c.192C>G	p.Arg64Arg	synonymous_variant	Exon 2 of 3		NP_001269418.1	Q495M9B4DL95
USH1G	XM_011524296.2 link	c.192C>G	p.Arg64Arg	synonymous_variant	Exon 2 of 3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH1G	ENST00000614341.5 link	c.501C>G	p.Arg167Arg	synonymous_variant	Exon 2 of 3	1	NM_173477.5	ENSP00000480279.1	Q495M9
USH1G	ENST00000579243.1 link	n.*100C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2		ENSP00000462568.1	J3KSN5
USH1G	ENST00000579243.1 link	n.*100C>G		3_prime_UTR_variant	Exon 2 of 3	2		ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00157

AC:

388

AN:

246718

Hom.:

AF XY:

0.00172

AC XY:

230

AN XY:

134108

show subpopulations

Gnomad AFR exome

AF:

0.000505

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00244

AC:

3559

AN:

1457702

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1760

AN XY:

725122

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00220

Gnomad4 FIN exome

AF:

0.00153

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152372

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00104

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00270

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00162

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH1G: BP4, BP7 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg167Arg in exon 2 of USH1G: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.2% (46/24364) of F innish chromosomes, 0.2% (68/30696) of South Asian chromosomes, and 0.2% (266/12 5092) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomAD.broadinstitute.org; dbSNP rs141688757). -

Usher syndrome type 1G

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.1

DANN

Benign

0.81

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