rs876657709

Positions:

• chr6-75890208-GAA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004999.4(MYO6):​c.2814_2815del​(p.Arg939ThrfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYO6 NM_004999.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.90

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 18 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 6-75890208-GAA-G is Pathogenic according to our data. Variant chr6-75890208-GAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 228375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75890208-GAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.2814_2815del	p.Arg939ThrfsTer2	frameshift_variant	26/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.2814_2815del	p.Arg939ThrfsTer2	frameshift_variant	26/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250946 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

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

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25227905) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 12, 2022	ClinVar contains an entry for this variant (Variation ID: 228375). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 25227905). This variant is present in population databases (rs753233152, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg939Thrfs*2) in the MYO6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO6 are known to be pathogenic (PMID: 12687499, 18348273, 23767834, 25999546, 30582396). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2016

The p.Arg939fs variant in MYO6 has been previously reported in 1 individual with nonsyndromic hearing loss and was found to segregate with disease in 14 affecte d family members in an autosomal dominant manner (Cheng 2014). It has also been identified in 1/66162 European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org). This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 939 and lead to a premature termination codon 2 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. Truncating or l oss-of-function variants in the MYO6 gene have been associated with autosomal re cessive congenital sensorineural hearing loss (Ahmed 2003) as well as autosomal dominant postlingual/late-onset progressive sensorineural hearing loss with vari able onset and severity (Hilgert 2008, Sanggaard 2008, Neveling 2013, Schrauwen 2013, Volk 2013). In summary, this variant meets our criteria to be classified a s pathogenic for dominantly inherited nonsyndromic hearing loss based upon the s egregation studies in the reported family and its predicted impact to the protei n. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs876657709; hg19: chr6-76599925;