NM_153700.2:c.1086C>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_153700.2(STRC):c.1086C>A(p.Tyr362*) 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: not found (cov: 1)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.11

Publications

0 publications found

Variant links:

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]

STRC Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 16
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

STRC links:

ENSG00000284772 (HGNC:):

ENSG00000284772 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-43616480-G-T is Pathogenic according to our data. Variant chr15-43616480-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 228401.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 link	c.1086C>A	p.Tyr362*	stop_gained	Exon 4 of 29	ENST00000450892.7	NP_714544.1	Q7RTU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.1086C>A	p.Tyr362*	stop_gained	Exon 4 of 29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9
ENSG00000284772	ENST00000643290.1 link	n.*1217+32C>A		intron_variant	Intron 6 of 8			ENSP00000495476.1		A0A2R8Y6Q2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000325

AC:

AN:

307552

Hom.:

Cov.:

AF XY:

0.00000617

AC XY:

AN XY:

162062

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8828

American (AMR)

AF:

0.00

AC:

AN:

14446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9342

East Asian (EAS)

AF:

0.00

AC:

AN:

18116

South Asian (SAS)

AF:

0.00

AC:

AN:

41974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1316

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

179906

Other (OTH)

AF:

0.00

AC:

AN:

17470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rare genetic deafness

Pathogenic:1

Nov 19, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Tyr362X variant in STRC has not been previously reported in individuals wi th hearing loss. Data from large population studies is insufficient to assess th e frequency of this variant. This nonsense variant leads to a premature terminat ion codon at position 362, which is predicted to lead to a truncated or absent p rotein. In summary, this variant meets our criteria to be classified as pathoge nic for autosomal recessive hearing loss based on the predicted impact of the va riant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.84

PhyloP100

1.1

Vest4

0.62

GERP RS

3.8

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over