rs1555447538

Positions:

• chr15-43611493-ACTCACATCGTGCCTAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_153700.2(STRC):​c.3128_3138+5del variant causes a splice donor, splice donor 5th base, coding sequence, intron change. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 4)
• Consequence: STRC NM_153700.2 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.007132132 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 15-43611493-ACTCACATCGTGCCTAG-A is Pathogenic according to our data. Variant chr15-43611493-ACTCACATCGTGCCTAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505025.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.3128_3138+5del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	12/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.3128_3138+5del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	12/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes Cov.: 4

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 02, 2016

The c.3128_3138+5del variant in STRC has been reported in one individual with he aring loss (Mandelker 2014, LMM data). Data from large population studies are i nsufficient to assess the frequency of this variant. This variant is a deletion of 16 nucleotides encompassing 11 nucleotides of exon 12 and 5 nucleotides of in tron 12, which includes the invariant region (+/- 1/2) of the splice consensus s equence. This deletion is predicted to cause altered splicing leading to an abno rmal or absent protein. Loss-of-function variants in the STRC gene are causative for autosomal recessive hearing loss. In summary, although additional studies a re required to fully establish its clinical significance, this variant is likely pathogenic. -

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: rs1555447538; hg19: chr15-43903691;