11-17494121-T-C

Position:

• chr11-17494121-T-C

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.*211A>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 0.445 in 612,558 control chromosomes in the GnomAD database, including 61,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15358 hom., cov: 32)
  • Exomes 𝑓: 0.44 (46517 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.07

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=-0.98).
• BP6: Variant 11-17494121-T-C is Benign according to our data. Variant chr11-17494121-T-C is described in ClinVar as [Benign]. Clinvar id is 303796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_005709.4	c.*243A>G		3_prime_UTR_variant	21/21	ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4	c.*211A>G		3_prime_UTR_variant	27/27	ENST00000005226.12	NP_710142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.*211A>G		3_prime_UTR_variant	27/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.*243A>G		3_prime_UTR_variant	21/21	1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67730 AN: 151572 Hom.: 15343 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.444 AC: 204515 AN: 460864 Hom.: 46517 Cov.: 5 AF XY: 0.440 AC XY: 107472 AN XY: 244234

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.474

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.473

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.447 AC: 67774 AN: 151694 Hom.: 15358 Cov.: 32 AF XY: 0.446 AC XY: 33044 AN XY: 74134

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.369

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.445

Alfa AF: 0.455 Hom.: 21282

Bravo AF: 0.439

Asia WGS AF: 0.357 AC: 1241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Jul 07, 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. -

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	-0.98
CADD	Benign	0.032
DANN	Benign	0.51

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1055581; hg19: chr11-17515668; COSMIC: COSV50046005; COSMIC: COSV50046005;