rs4757539

chr11-17523544-A-Gchr11-17523544-A-T

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.760-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,533,868 control chromosomes in the GnomAD database, including 262,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24543 hom., cov: 32)
  • Exomes 𝑓: 0.59 (238231 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.902

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=-0.93).
• BP6: Variant 11-17523544-A-G is Benign according to our data. Variant chr11-17523544-A-G is described in ClinVar as [Benign]. Clinvar id is 678879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.760-66T>C		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.760-66T>C		intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.760-66T>C		intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.760-66T>C		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86192 AN: 151922 Hom.: 24496 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.586 AC: 810089 AN: 1381828 Hom.: 238231 AF XY: 0.589 AC XY: 406475 AN XY: 690348

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.629

Gnomad4 ASJ exome AF: 0.536

Gnomad4 EAS exome AF: 0.689

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.527

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.587

GnomAD4 genome AF: 0.568 AC: 86298 AN: 152040 Hom.: 24543 Cov.: 32 AF XY: 0.572 AC XY: 42493 AN XY: 74328

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.561

Alfa AF: 0.565 Hom.: 3990

Bravo AF: 0.568

Asia WGS AF: 0.705 AC: 2450 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

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. -

Usher syndrome type 1C 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	-0.93
Cadd	Benign	0.48
Dann	Benign	0.40

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: rs4757539; hg19: chr11-17545091; COSMIC: COSV50018456; COSMIC: COSV50018456;