rs727505015

Positions:

• chr6-75907634-CTGCTGG-CATCCTACATACTTAAAATTTCTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004999.4(MYO6):​c.3207_3212delinsATCCTACATACTTAAAATTTCTT​(p.Ala1070SerfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO6 NM_004999.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.53

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-75907635-TGCTGG-ATCCTACATACTTAAAATTTCTT is Pathogenic according to our data. Variant chr6-75907635-TGCTGG-ATCCTACATACTTAAAATTTCTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.3207_3212delinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift_variant	31/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.3207_3212delinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift_variant	31/35	1	NM_004999.4	ENSP00000358994	A1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

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

Sep 05, 2014

The Ala1070fs variant in MYO6 has not been previously reported in individuals wi th hearing loss or in large population studies. This variant is predicted to cau se a frameshift, which alters the protein's amino acid sequence beginning at cod on 1070 and leads to a premature stop codon 46 codons downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Truncating or loss of function variants in the MYO6 gene have been associated with autosomal reces sive hearing loss as well as autosomal dominant hearing loss (Hilgert 2008, Sang gaard 2008, Neveling 2013, Schrauwen 2013, Volk 2013). Although it has been sugg ested that dominant variants in MYO6 act in a dominant-negative manner (Hilgert 2008), the exact mechanism of pathogenesis has not been fully elucidated. In sum mary, although additional studies are required to fully establish its clinical s ignificance, 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: rs727505015; hg19: chr6-76617352;