rs1021413948

Variant names:

• chr15-43614194-ACCTGCAGCTTCC-A
• rs1021413948
• NM_153700.2:c.2303_2313+1delGGAAGCTGCAGG

Your query was ambiguous. Multiple possible variants found:

• chr15-43614194-ACCTGCAGCTTCC-A
• chr15-43614194-ACCTGCAGCTTCC-ACCTGCAGCTTCCCCTGCAGCTTCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_153700.2(STRC):​c.2303_2313+1delGGAAGCTGCAGG​(p.Lys769fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 2)
  • Exomes 𝑓: 0.0013 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0640

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]

ENSG00000284772 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	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
ENSG00000284772	ENST00000643290.1	n.*1524_*1535delGGAAGCTGCAGG		downstream_gene_variant				ENSP00000495476.1

Frequencies

GnomAD3 genomes AF: 0.000870 AC: 6 AN: 6900 Hom.: 0 Cov.: 2

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

GnomAD3 exomes AF: 0.000248 AC: 10 AN: 40334 Hom.: 0 AF XY: 0.000291 AC XY: 6 AN XY: 20618

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 SAS exome AF: 0.000224

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.: 9 AF XY: 0.00132 AC XY: 184 AN XY: 139404

Gnomad4 AFR exome AF: 0.00729

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.000314

Gnomad4 EAS exome AF: 0.00743

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.000488

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000870 AC: 6 AN: 6894 Hom.: 0 Cov.: 2 AF XY: 0.000966 AC XY: 3 AN XY: 3106

Gnomad4 AFR AF: 0.00803

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000268

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00192 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1021413948; hg19: chr15-43906392;