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. The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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

Specifications for MYO6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift missense	Exon 31 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.3234_3239delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1079SerfsTer46	frameshift missense	Exon 32 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.3234_3239delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1079SerfsTer46	frameshift missense	Exon 32 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.3207_3212delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1070SerfsTer46	frameshift missense	Exon 31 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.3138_3143delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1047SerfsTer46	frameshift missense	Exon 28 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.3234_3239delTGCTGGinsATCCTACATACTTAAAATTTCTT	p.Ala1079SerfsTer46	frameshift missense	Exon 32 of 36	ENSP00000499278.1	A0A590UJ40

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727505015;

hg19: chr6-76617352;