rs201644674

Positions:

• chr17-74920270-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173477.5(USH1G):​c.566G>A​(p.Arg189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,603,326 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (22 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.34

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00816673).
• BP6: Variant 17-74920270-C-T is Benign according to our data. Variant chr17-74920270-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48134.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr17-74920270-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (187/152388) while in subpopulation SAS AF= 0.00786 (38/4832). AF 95% confidence interval is 0.00589. There are 2 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5	c.566G>A	p.Arg189Gln	missense_variant	2/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.257G>A	p.Arg86Gln	missense_variant	2/3		NP_001269418.1
USH1G	XM_011524296.2	c.257G>A	p.Arg86Gln	missense_variant	2/3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.566G>A	p.Arg189Gln	missense_variant	2/3	1	NM_173477.5	ENSP00000480279.1
USH1G	ENST00000579243.1	n.*165G>A		non_coding_transcript_exon_variant	2/3	2		ENSP00000462568.1
USH1G	ENST00000579243.1	n.*165G>A		3_prime_UTR_variant	2/3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152270 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00212 AC: 505 AN: 238722 Hom.: 2 AF XY: 0.00261 AC XY: 342 AN XY: 130796

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00293

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.00856

Gnomad FIN exome AF: 0.0000668

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00248 AC: 3594 AN: 1450938 Hom.: 22 Cov.: 41 AF XY: 0.00264 AC XY: 1904 AN XY: 722092

Gnomad4 AFR exome AF: 0.000778

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00284

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00837

Gnomad4 FIN exome AF: 0.0000915

Gnomad4 NFE exome AF: 0.00232

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152388 Hom.: 2 Cov.: 32 AF XY: 0.00131 AC XY: 98 AN XY: 74526

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00115

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00188 AC: 16

ExAC AF: 0.00218 AC: 264

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	This variant is associated with the following publications: (PMID: 28912962) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	USH1G: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2015	p.Arg189Gln in exon 2 of USH1G: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (137/16376) of South Asian chr omosomes and 0.2% (113/63034) of European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201644674). -

Usher syndrome type 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

USH1G-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.27	T
Polyphen		0.90	P
Vest4		0.30
MVP		0.26
ClinPred		0.014	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.35

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: rs201644674; hg19: chr17-72916365;