rs876657726

Variant names:

• chr15-43610317-G-A
• rs876657726
• NM_153700.2:c.3493C>T

Variant summary

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

The NM_153700.2(STRC):​c.3493C>T​(p.Gln1165*) variant causes a stop gained change. 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: not found (cov: 13)
  • Exomes 𝑓: 0.0000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.81

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 15-43610317-G-A is Pathogenic according to our data. Variant chr15-43610317-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228403.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.3493C>T	p.Gln1165*	stop_gained	Exon 15 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.3493C>T	p.Gln1165*	stop_gained	Exon 15 of 29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000175 AC: 1 AN: 572742 Hom.: 0 Cov.: 8 AF XY: 0.00000331 AC XY: 1 AN XY: 301956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 13

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Jun 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln1165X variant in STRC has not been previously reported in individuals w ith hearing loss. Data from large population studies is insufficient to assess t he frequency of this variant. This nonsense variant leads to a premature termin ation codon at position 1165, which is predicted to lead to a truncated or absen t protein. Loss of function of the STRC gene is an established disease mechanism in hearing loss. In summary, this variant meets criteria to be classified as pa thogenic for hearing loss in an autosomal recessive manner based upon predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.70
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876657726; hg19: chr15-43902515;