11-17494091-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153676.4(USH1C):c.*241C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 564,456 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (2 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.496

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.*273C>G		3_prime_UTR_variant	21/21	ENST00000318024.9
USH1C	NM_153676.4	c.*241C>G		3_prime_UTR_variant	27/27	ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.*241C>G		3_prime_UTR_variant	27/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.*273C>G		3_prime_UTR_variant	21/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000932 AC: 384 AN: 412186 Hom.: 2 Cov.: 4 AF XY: 0.000864 AC XY: 189 AN XY: 218630

Gnomad4 AFR exome AF: 0.000173

Gnomad4 AMR exome AF: 0.0000536

Gnomad4 ASJ exome AF: 0.000161

Gnomad4 EAS exome AF: 0.00196

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.00755

Gnomad4 NFE exome AF: 0.000403

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000741 Hom.: 0

Bravo AF: 0.000200

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 1C 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	-0.86
Cadd	Benign	5.1
Dann	Benign	0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs551263680; hg19: chr11-17515638;