chr11-17494146-G-A

Variant names:

• chr11-17494146-G-A
• rs1055577
• ENST00000526313.5:n.*591C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.*186C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 682,734 control chromosomes in the GnomAD database, including 67,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14484 hom., cov: 32)
  • Exomes 𝑓: 0.44 (53507 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.501
• Publications: 14 publications found

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]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-17494146-G-A is Benign according to our data. Variant chr11-17494146-G-A is described in ClinVar as [Benign]. Clinvar id is 303797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.*186C>T		3_prime_UTR_variant	Exon 27 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.*218C>T		3_prime_UTR_variant	Exon 21 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.*186C>T		3_prime_UTR_variant	Exon 27 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.*218C>T		3_prime_UTR_variant	Exon 21 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65721 AN: 151590 Hom.: 14476 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.444 AC: 235550 AN: 531024 Hom.: 53507 Cov.: 6 AF XY: 0.440 AC XY: 123860 AN XY: 281360

African (AFR) AF: 0.413 AC: 5751 AN: 13926

American (AMR) AF: 0.333 AC: 8671 AN: 26058

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 7774 AN: 16390

East Asian (EAS) AF: 0.299 AC: 9224 AN: 30880

South Asian (SAS) AF: 0.376 AC: 20037 AN: 53308

European-Finnish (FIN) AF: 0.471 AC: 19346 AN: 41112

Middle Eastern (MID) AF: 0.401 AC: 868 AN: 2164

European-Non Finnish (NFE) AF: 0.475 AC: 151394 AN: 318952

Other (OTH) AF: 0.442 AC: 12485 AN: 28234

GnomAD4 genome AF: 0.433 AC: 65757 AN: 151710 Hom.: 14484 Cov.: 32 AF XY: 0.433 AC XY: 32106 AN XY: 74150

African (AFR) AF: 0.409 AC: 16900 AN: 41314

American (AMR) AF: 0.365 AC: 5579 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1683 AN: 3464

East Asian (EAS) AF: 0.288 AC: 1486 AN: 5154

South Asian (SAS) AF: 0.374 AC: 1801 AN: 4818

European-Finnish (FIN) AF: 0.485 AC: 5105 AN: 10524

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31801 AN: 67858

Other (OTH) AF: 0.431 AC: 910 AN: 2110

Alfa AF: 0.449 Hom.: 20097

Bravo AF: 0.424

Asia WGS AF: 0.349 AC: 1216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Usher syndrome type 1C Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.46
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1055577; hg19: chr11-17515693; COSMIC: COSV50015733; COSMIC: COSV50015733;