15-43611237-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PP3_ModeratePP5_Very_Strong

The NM_153700.2(STRC):c.3217C>T(p.Arg1073*) 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 0.000025 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.392

Publications

1 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:

ENSG00000309475 (HGNC:):

ENSG00000309475 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

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

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-43611237-G-A is Pathogenic according to our data. Variant chr15-43611237-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 228402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.3217C>T	p.Arg1073*	stop_gained	Exon 13 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.3217C>T	p.Arg1073*	stop_gained	Exon 13 of 29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9

Frequencies

GnomAD3 genomes

AF:

0.0000246

AC:

AN:

122150

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000542

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000104

AC:

AN:

95826

AF XY:

0.0000200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000296

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000698

AC:

AN:

716188

Hom.:

Cov.:

AF XY:

0.00000540

AC XY:

AN XY:

370656

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:

21186

American (AMR)

AF:

0.00

AC:

AN:

33132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18754

East Asian (EAS)

AF:

0.00

AC:

AN:

32708

South Asian (SAS)

AF:

0.0000488

AC:

AN:

61450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2694

European-Non Finnish (NFE)

AF:

0.00000418

AC:

AN:

478286

Other (OTH)

AF:

0.00

AC:

AN:

35632

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000224764), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000245

AC:

AN:

122264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

58034

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

35144

American (AMR)

AF:

0.00

AC:

AN:

11696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2794

East Asian (EAS)

AF:

0.00

AC:

AN:

4084

South Asian (SAS)

AF:

0.00

AC:

AN:

3126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0000542

AC:

AN:

55316

Other (OTH)

AF:

0.00

AC:

AN:

1508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 16

Pathogenic:2

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 28, 2023

King Laboratory, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant occurred in compound heterozygosity with an STRC full gene deletion in two siblings with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). The family has no other history of hearing loss. This variant is a nonsense leading to an early stop at position 1073 of 1775 in the stereocilin protein. As of January 2023, this variant has been reported to ClinVar as pathogenic and is found in 1 heterozygote on gnomAD. Based on the prediction that this variant leads to a truncated protein, compound heterozygosity with a loss-of-function variant, co-segregation within the family, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. -

STRC-related disorder

Pathogenic:1

Dec 04, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The STRC c.3217C>T variant is predicted to result in premature protein termination (p.Arg1073*). This variant has been reported as pathogenic in patients with nonsyndromic hearing loss (Marková et al. 2018. PubMed ID: 29425068; Table S1, Safka Brozkova et al. 2020. PubMed ID: 32860223). This variant is reported in 0.0030% of alleles in individuals of European (Non-Finnish) descent in gnomAD, although due to sequence paralogy the allele frequency estimates at this locus may be unreliable. Nonsense variants in STRC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Nov 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg1073X variant in STRC has been previously reported by our laboratory in 1 individual with hearing loss, who was compound heterozygous for a second path ogenic variant in STRC. Data from large population studies is insufficient to as sess the frequency of this variant. This nonsense variant leads to a premature t ermination codon at position 1073, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as path ogenic for hearing loss in an autosomal recessive manner based on its predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Benign

0.85

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.018

PhyloP100

-0.39

Vest4

0.72

GERP RS

-8.3

Mutation Taster

=22/178

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.94

Position offset: 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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over