11-17501927-G-A

Position:

• chr11-17501927-G-A

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.2226+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 1,612,542 control chromosomes in the GnomAD database, including 4,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (343 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3835 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.423

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-17501927-G-A is Benign according to our data. Variant chr11-17501927-G-A is described in ClinVar as [Benign]. Clinvar id is 47995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2226+12C>T		intron_variant		ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1326+12C>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2226+12C>T		intron_variant		5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1326+12C>T		intron_variant		1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8705 AN: 152030 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0542

GnomAD3 exomes AF: 0.0645 AC: 16163 AN: 250542 Hom.: 921 AF XY: 0.0711 AC XY: 9620 AN XY: 135338

Gnomad AFR exome AF: 0.0663

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0275

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0587

GnomAD4 exome AF: 0.0599 AC: 87410 AN: 1460394 Hom.: 3835 Cov.: 31 AF XY: 0.0636 AC XY: 46170 AN XY: 726474

Gnomad4 AFR exome AF: 0.0633

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0362

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0335

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.0641

GnomAD4 genome AF: 0.0572 AC: 8701 AN: 152148 Hom.: 343 Cov.: 32 AF XY: 0.0579 AC XY: 4307 AN XY: 74394

Gnomad4 AFR AF: 0.0636

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.0381

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.0530

Gnomad4 OTH AF: 0.0551

Alfa AF: 0.0564 Hom.: 438

Bravo AF: 0.0549

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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 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	-0.83
CADD	Benign	12
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17703528; hg19: chr11-17523474; COSMIC: COSV50046257;