rs727505015

Variant names:

• chr6-75907635-TGCTGG-ATCCTACATACTTAAAATTTCTT
• rs727505015
• NM_004999.4:c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_004999.4(MYO6):​c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT​(p.Ala1070SerfsTer46) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1069A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO6 NM_004999.4 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.53
• Publications: 0 publications found

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]

MYO6 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 179643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift_variant, missense_variant	Exon 31 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift_variant, missense_variant	Exon 31 of 35	1	NM_004999.4	ENSP00000358994.3

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

Sep 05, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

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

Other links and lift over

dbSNP: rs727505015; hg19: chr6-76617352;