11-17494286-A-G

Variant names:

• chr11-17494286-A-G
• rs1055574
• ENST00000526313.5:n.*451T>C

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.*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
• Publications: 21 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 11-17494286-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 rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.*46T>C		3_prime_UTR_variant	Exon 27 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.*78T>C		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.*46T>C		3_prime_UTR_variant	Exon 27 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.*78T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_005709.4	ENSP00000317018.4

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

GnomAD2 exomes AF: 0.423 AC: 92866 AN: 219628 AF XY: 0.427

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 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

African (AFR) AF: 0.408 AC: 13491 AN: 33046

American (AMR) AF: 0.322 AC: 13536 AN: 42026

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12286 AN: 25756

East Asian (EAS) AF: 0.303 AC: 11840 AN: 39062

South Asian (SAS) AF: 0.381 AC: 31583 AN: 82824

European-Finnish (FIN) AF: 0.475 AC: 24774 AN: 52160

Middle Eastern (MID) AF: 0.374 AC: 2089 AN: 5590

European-Non Finnish (NFE) AF: 0.476 AC: 523650 AN: 1099684

Other (OTH) AF: 0.446 AC: 26588 AN: 59614

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

African (AFR) AF: 0.412 AC: 17085 AN: 41480

American (AMR) AF: 0.367 AC: 5611 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1523 AN: 5158

South Asian (SAS) AF: 0.382 AC: 1839 AN: 4816

European-Finnish (FIN) AF: 0.488 AC: 5157 AN: 10562

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31959 AN: 67952

Other (OTH) AF: 0.431 AC: 908 AN: 2108

Alfa AF: 0.451 Hom.: 50437

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 12, 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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	3.1
DANN	Benign	0.55
PhyloP100		-0.087
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: rs1055574; hg19: chr11-17515833; COSMIC: COSV50036203; COSMIC: COSV50036203;