rs45552041

chr11-17527157-C-Achr11-17527157-C-Gchr11-17527157-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_153676.4(USH1C):c.496+66G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 55,774 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 0)
  • Exomes 𝑓: 0.035 (383 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0730

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17527157-C-A is Benign according to our data. Variant chr11-17527157-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 678907.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0057 (318/55774) while in subpopulation NFE AF= 0.0077 (208/27028). AF 95% confidence interval is 0.00684. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.496+66G>T		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.496+66G>T		intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.496+66G>T		intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.496+66G>T		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 319 AN: 55730 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00926

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.00424

Gnomad EAS AF: 0.00233

Gnomad SAS AF: 0.00472

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.0283

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00754

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0348 AC: 16598 AN: 477172 Hom.: 383 Cov.: 4 AF XY: 0.0344 AC XY: 8163 AN XY: 237280

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.00950

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.0665

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0397

GnomAD4 genome AF: 0.00570 AC: 318 AN: 55774 Hom.: 2 Cov.: 0 AF XY: 0.00573 AC XY: 154 AN XY: 26886

Gnomad4 AFR AF: 0.00175

Gnomad4 AMR AF: 0.00518

Gnomad4 ASJ AF: 0.00424

Gnomad4 EAS AF: 0.00234

Gnomad4 SAS AF: 0.00473

Gnomad4 FIN AF: 0.00952

Gnomad4 NFE AF: 0.00770

Gnomad4 OTH AF: 0.00744

Alfa AF: 0.0408 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.3
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45552041; hg19: chr11-17548704; COSMIC: COSV50014841;