ENST00000440125.5:n.*555C>A – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The ENST00000440125.5(STRC):n.*555C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., cov: 7)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STRC
ENST00000440125.5 non_coding_transcript_exon

Scores

Splicing: ADA: 0.9691

Clinical Significance

Uncertain significance criteria provided, single submitter U: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:

ENSG00000309475 (HGNC:):

ENSG00000309475 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.2481-3C>A		splice_region_variant, intron_variant	Intron 7 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.2481-3C>A		splice_region_variant, intron_variant	Intron 7 of 28	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes

AF:

0.0000191

AC:

AN:

52310

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:

0.0000325

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

263840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

143552

African (AFR)

AF:

0.00

AC:

AN:

5324

American (AMR)

AF:

0.00

AC:

AN:

14296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5618

East Asian (EAS)

AF:

0.00

AC:

AN:

10842

South Asian (SAS)

AF:

0.00

AC:

AN:

43804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

794

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

160804

Other (OTH)

AF:

0.00

AC:

AN:

11996

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000191

AC:

AN:

52310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

24548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

5896

American (AMR)

AF:

0.00

AC:

AN:

5288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1514

East Asian (EAS)

AF:

0.00

AC:

AN:

2030

South Asian (SAS)

AF:

0.00

AC:

AN:

1314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.0000325

AC:

AN:

30748

Other (OTH)

AF:

0.00

AC:

AN:

648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2481-3C>A variant in STRC has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to asses s the frequency of this variant in the general population. This variant is loca ted in the 3' splice region. Computational tools do not suggest an impact to spl icing. However, this information is not predictive enough to rule out pathogenic ity. In summary, the clinical significance of the c.2481-3C>A variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

8.0

(source)

DANN

Benign

0.70

PhyloP100

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.59

Position offset: -3

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