Variant summary

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

The NM_153700.2(STRC):c.3484delT(p.Trp1162GlyfsTer46) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., cov: 12)

Exomes 𝑓: 0.0000081 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.34

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:

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 15-43610325-CA-C is Pathogenic according to our data. Variant chr15-43610325-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 179717.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153700.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	NM_153700.2	MANE Select	c.3484delT	p.Trp1162GlyfsTer46	frameshift	Exon 15 of 29	NP_714544.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STRC	ENST00000450892.7	TSL:5 MANE Select	c.3484delT	p.Trp1162GlyfsTer46	frameshift	Exon 15 of 29	ENSP00000401513.2
STRC	ENST00000440125.5	TSL:1	n.*1276delT		non_coding_transcript_exon	Exon 14 of 28	ENSP00000394866.1
STRC	ENST00000440125.5	TSL:1	n.*1276delT		3_prime_UTR	Exon 14 of 28	ENSP00000394866.1

Frequencies

GnomAD3 genomes

AF:

0.0000194

AC:

AN:

103278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000430

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:

0.0000192

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000957

AC:

AN:

104522

AF XY:

0.00

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000813

AC:

AN:

615162

Hom.:

Cov.:

AF XY:

0.00000312

AC XY:

AN XY:

320916

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:

15814

American (AMR)

AF:

0.00

AC:

AN:

30764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14062

East Asian (EAS)

AF:

0.00

AC:

AN:

23718

South Asian (SAS)

AF:

0.00

AC:

AN:

64066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2182

European-Non Finnish (NFE)

AF:

0.0000123

AC:

AN:

407062

Other (OTH)

AF:

0.00

AC:

AN:

27122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000064948), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

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:

0.0000194

AC:

AN:

103278

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

48764

show subpopulations

African (AFR)

AF:

0.0000430

AC:

AN:

23256

American (AMR)

AF:

0.00

AC:

AN:

9372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2576

East Asian (EAS)

AF:

0.00

AC:

AN:

4182

South Asian (SAS)

AF:

0.00

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

228

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

52014

Other (OTH)

AF:

0.00

AC:

AN:

1274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000613

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.3

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_153700.2:c.3484delT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over