rs397517045

Positions:

• chr6-75879851-T-TG

Variant summary

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

The NM_004999.4(MYO6):​c.2111dupG​(p.Tyr705fs) 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: 9.48

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 6-75879851-T-TG is Pathogenic according to our data. Variant chr6-75879851-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45141.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.2111dupG	p.Tyr705fs	frameshift_variant	21/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2111dupG	p.Tyr705fs	frameshift_variant	21/35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jul 18, 2018

The Tyr705fs variant in MYO6 has been reported by our laboratory in 1 individual with hearing loss and segregated in two affected family members (this family). It was absent from large population studies. This frameshift variant is expected to alter the protein?s amino acid sequence beginning at position 705 and lead t o a premature termination codon 9 amino acids downstream. This alteration is the n predicted to lead to a truncated or absent protein. Loss-of-function variants in the MYO6 gene have been strongly associated to autosomal dominant hearing los s (Sanggaard 2008, Cheng 2014, Miyagawa 2015, Yang 2013, Volk 2013), and there i s also evidence that biallelic occurrence may result in a more severe hearing lo ss (Ahmed 2003, Yan 2016, Yang 2013 ). In summary, this variant is likely pathog enic for autosomal dominant hearing loss, though additional studies are required to fully establish its clinical significance. ACMG/AMP Criteria applied: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517045; hg19: chr6-76589568;