rs75157409

chr11-17533258-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):c.101A>G(p.His34Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,556 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H34H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (8 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.31

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008830547).
• BP6: Variant 11-17533258-T-C is Benign according to our data. Variant chr11-17533258-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17533258-T-C is described in Lovd as [Likely_benign]. Variant chr11-17533258-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00483 (735/152190) while in subpopulation AFR AF= 0.0162 (674/41518). AF 95% confidence interval is 0.0152. There are 8 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.101A>G	p.His34Arg	missense_variant	2/27	ENST00000005226.12
USH1C	NM_005709.4	c.101A>G	p.His34Arg	missense_variant	2/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.101A>G	p.His34Arg	missense_variant	2/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.101A>G	p.His34Arg	missense_variant	2/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152072 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251296 Hom.: 1 AF XY: 0.00118 AC XY: 160 AN XY: 135830

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000645 AC: 943 AN: 1461366 Hom.: 8 Cov.: 31 AF XY: 0.000616 AC XY: 448 AN XY: 727056

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00483 AC: 735 AN: 152190 Hom.: 8 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74422

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000995 Hom.: 1

Bravo AF: 0.00565

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	This variant is associated with the following publications: (PMID: 24498627) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1C Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 11, 2019	- -
Likely benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2012

His34Arg in Exon 02 of USH1C: This variant is not expected to have clinical sign ificance because it has been identified in 1.5% (57/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs75157409). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
MetaRNN	Benign	0.0088	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.024	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;.
Polyphen		0.77	P;.;P;.;.
Vest4		0.92
MVP		0.27
MPC		0.37
ClinPred		0.015	T
GERP RS		5.1
Varity_R		0.73
gMVP		0.80

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: rs75157409; hg19: chr11-17554805;