rs727503444

chr15-43608091-G-Achr15-43608091-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153700.2(STRC):c.3670C>T(p.Arg1224Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000696 in 1,609,882 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000047 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000072 (1 hom.)
• Consequence: STRC NM_153700.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.40

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-43608091-G-A is Pathogenic according to our data. Variant chr15-43608091-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 165315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.3670C>T	p.Arg1224Ter	stop_gained	17/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.3670C>T	p.Arg1224Ter	stop_gained	17/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000469 AC: 7 AN: 149340 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000970

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250780 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135586

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000719 AC: 105 AN: 1460542 Hom.: 1 Cov.: 32 AF XY: 0.0000826 AC XY: 60 AN XY: 726630

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000469 AC: 7 AN: 149340 Hom.: 0 Cov.: 21 AF XY: 0.0000274 AC XY: 2 AN XY: 72954

Gnomad4 AFR AF: 0.0000255

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000970

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000907 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21078986, 22147502, 31216405, 29339441) -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 28, 2014

The p.Arg1224X variant in STRC has been previously identified by our laboratory in 2 Caucasian individuals with hearing loss, both of whom carried a second path ogenic variant in STRC on the other allele. It was absent from large population studies. This nonsense variant leads to a premature termination codon at positio n 1224, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based on its predicted impact to the protein. -

Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

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Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.75	D
MutationTaster	Benign	1.0	D;A;A
Vest4		0.86
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503444; hg19: chr15-43900289; COSMIC: COSV68659573; COSMIC: COSV68659573;