rs771264491

chr15-43618042-G-Achr15-43618042-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_153700.2(STRC):c.379C>T(p.Arg127Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 3.17

Genes affected

STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-43618042-G-A is Pathogenic according to our data. Variant chr15-43618042-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 505325.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.379C>T	p.Arg127Ter	stop_gained	2/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.379C>T	p.Arg127Ter	stop_gained	2/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 11 AN: 149836 Hom.: 0 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000599

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000156 AC: 224 AN: 1436238 Hom.: 0 Cov.: 27 AF XY: 0.000149 AC XY: 106 AN XY: 713694

Gnomad4 AFR exome AF: 0.0000927

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000359

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.000445

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000734 AC: 11 AN: 149918 Hom.: 0 Cov.: 19 AF XY: 0.0000958 AC XY: 7 AN XY: 73072

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.0000599

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000480 Hom.: 0

ExAC AF: 0.0000426 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 01, 2016

The p.Arg127X variant in STRC has not been previously reported in individuals wi th hearing loss. Data from large population studies are insufficient to assess t he frequency of this variant in the general population accurately. This nonsens e variant leads to a premature termination codon at position 127, which is predi cted to lead to a truncated or absent protein. Loss of function of the STRC gene is an established disease mechanism in autosomal recessive hearing loss. In sum mary, this variant meets criteria to be classified as pathogenic for hearing los s in an autosomal recessive manner. -

Autosomal recessive nonsyndromic hearing loss 16 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Pathogenic and reported on 09-01-2016 by Lab or GTR ID 21766. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;A;D
Vest4		0.81
GERP RS		2.7

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: rs771264491; hg19: chr15-43910240; COSMIC: COSV101405456; COSMIC: COSV101405456;