11-17494286-A-G

Position:

• chr11-17494286-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.*46T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,591,812 control chromosomes in the GnomAD database, including 167,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14730 hom., cov: 33)
  • Exomes 𝑓: 0.46 (152964 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0870

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 (BayesDel_noAF=-0.9).
• BP6: Variant 11-17494286-A-G is Benign according to our data. Variant chr11-17494286-A-G is described in ClinVar as [Benign]. Clinvar id is 262730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.*78T>C		3_prime_UTR_variant	21/21	ENST00000318024.9
USH1C	NM_153676.4	c.*46T>C		3_prime_UTR_variant	27/27	ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.*46T>C		3_prime_UTR_variant	27/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.*78T>C		3_prime_UTR_variant	21/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66227 AN: 151932 Hom.: 14720 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.432

GnomAD3 exomes AF: 0.423 AC: 92866 AN: 219628 Hom.: 20051 AF XY: 0.427 AC XY: 50463 AN XY: 118104

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.458 AC: 659837 AN: 1439762 Hom.: 152964 Cov.: 32 AF XY: 0.457 AC XY: 326077 AN XY: 714094

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.477

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.475

Gnomad4 NFE exome AF: 0.476

Gnomad4 OTH exome AF: 0.446

GnomAD4 genome AF: 0.436 AC: 66266 AN: 152050 Hom.: 14730 Cov.: 33 AF XY: 0.435 AC XY: 32367 AN XY: 74322

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.431

Alfa AF: 0.453 Hom.: 32456

Bravo AF: 0.425

Asia WGS AF: 0.354 AC: 1233 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -

Usher syndrome type 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1055574; hg19: chr11-17515833; COSMIC: COSV50036203; COSMIC: COSV50036203;