chr17-74920335-G-C

Position:

• chr17-74920335-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.875

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]

ACMG classification

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, Uncertain_significance=1, Benign=2}. 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/exons	MANE	Protein	UniProt
USH1G	NM_173477.5	c.501C>G	p.Arg167Arg	synonymous_variant	2/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.192C>G	p.Arg64Arg	synonymous_variant	2/3		NP_001269418.1
USH1G	XM_011524296.2	c.192C>G	p.Arg64Arg	synonymous_variant	2/3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.501C>G	p.Arg167Arg	synonymous_variant	2/3	1	NM_173477.5	ENSP00000480279.1
USH1G	ENST00000579243.1	n.*100C>G		non_coding_transcript_exon_variant	2/3	2		ENSP00000462568.1
USH1G	ENST00000579243.1	n.*100C>G		3_prime_UTR_variant	2/3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152254 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.00172 AC XY: 230 AN XY: 134108

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.: 11 Cov.: 42 AF XY: 0.00243 AC XY: 1760 AN XY: 725122

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.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74514

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.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	USH1G: BP4, BP7 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2018	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Other links and lift over

dbSNP: rs141688757; hg19: chr17-72916430;