ENST00000440125.5:n.305_315+1delGGAAGCTGCAGG

Variant names:

Variant summary

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

The ENST00000440125.5(STRC):n.*305_*315+1delGGAAGCTGCAGG variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0013 ( 9 hom. )

Failed GnomAD Quality Control

Consequence

STRC
ENST00000440125.5 splice_region, non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.0640

Publications

2 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.2303_2313+1delGGAAGCTGCAGG	p.Lys769fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 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.2303_2313+1delGGAAGCTGCAGG	p.Lys769fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9
ENSG00000284772	ENST00000643290.1 link	n.1524_1535delGGAAGCTGCAGG		downstream_gene_variant				ENSP00000495476.1		A0A2R8Y6Q2

Frequencies

GnomAD3 genomes

AF:

0.000870

AC:

AN:

6900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00303

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000268

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000248

AC:

AN:

40334

AF XY:

0.000291

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.000386

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000321

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000600

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00133

AC:

351

AN:

263976

Hom.:

AF XY:

0.00132

AC XY:

184

AN XY:

139404

show subpopulations

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

African (AFR)

AF:

0.00729

AC:

AN:

4388

American (AMR)

AF:

0.00102

AC:

AN:

12788

Ashkenazi Jewish (ASJ)

AF:

0.000314

AC:

AN:

6366

East Asian (EAS)

AF:

0.00743

AC:

118

AN:

15874

South Asian (SAS)

AF:

0.00184

AC:

AN:

35274

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

16268

Middle Eastern (MID)

AF:

0.00120

AC:

AN:

836

European-Non Finnish (NFE)

AF:

0.000488

AC:

AN:

157926

Other (OTH)

AF:

0.00119

AC:

AN:

14256

⚠️ 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: 0.381

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000870

AC:

AN:

6894

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

3106

show subpopulations

African (AFR)

AF:

0.00803

AC:

AN:

498

American (AMR)

AF:

0.00

AC:

AN:

808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

142

East Asian (EAS)

AF:

0.00

AC:

AN:

516

South Asian (SAS)

AF:

0.00311

AC:

AN:

322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000268

AC:

AN:

3732

Other (OTH)

AF:

0.00

AC:

AN:

116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00192

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 02, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2303_2313+1del variant in STRC has been identified by our laboratory in one family with hearing loss who had a likely pathogenic variant on the remaining copy of STRC and segregated in 2 affected family members. This variant has also been previously identified in 5 individuals with hearing loss, one of whom was homozygous, another who was compound heterozygous for an additional missense variant in STRC, and three of whom were heterozygous and lacked a second STRC variant (Francey 2012 PMID: 22147502, Vona 2015 PMID: 26011646, Brozkova 2020 PMID: 32860223). Data from large population studies is insufficient to assess the frequency of this variant. This variant is a deletion of 12 nucleotides including the last 11 nucleotides of exon 6 and the nucleotide at the +1 position in the intron. While this variant deletes the invariant +1 position of the splice consensus sequence, splice prediction tools indicate that the variant may result in an alternate splice site which would delete 12 nucleotides and therefore could result in an in-frame deletion of four amino acid residues. Furthermore, the sequence of the 12 nucleotides that are deleted are part of a repetitive sequence, and species conservation shows that the four deleted amino acids are only present in 1 other mammal (chimpanzee). This raises the possibility that an alternate splice site at this position may not impact the protein. However, it is also possible that this variant would cause altered splicing leading to an abnormal or absent protein, due the fact that this variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.2303_2313+1del variant is uncertain due to the lack of frequency information and the conflicting conservation and computational data. ACMG/AMP Criteria applied: PM3, PP1_Moderate, PP3. -

Autosomal recessive nonsyndromic hearing loss 16

Uncertain:1

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.064

Mutation Taster

=13/187

disease causing (fs/PTC)

(source)

Splicing

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