rs121912558

Positions:

• chr6-75914119-C-T

Variant summary

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

The ENST00000369977.8(MYO6):​c.3496C>T​(p.Arg1166Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000342 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYO6 ENST00000369977.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.80

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 6-75914119-C-T is Pathogenic according to our data. Variant chr6-75914119-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8579.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-75914119-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.3496C>T	p.Arg1166Ter	stop_gained	34/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.3496C>T	p.Arg1166Ter	stop_gained	34/35	1	NM_004999.4	ENSP00000358994	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2020

Observed in heterozygous state in five patients with mild hearing loss, including four cases with onset between 29-35 years of age and family histories consistent with autosomal dominant inheritance, and one sporadic case with unknown age of onset and inheritance pattern (Miyagawa et al., 2015; Oka et al., 2020); R1166X segregated in two other heterozygous affected relatives in one of these families; Published functional studies demonstrate a damging effect resulting in a truncated protein with aberrant binding and localization (Arden et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 25999546, 32143290, 12687499, 18348273, 27474411, 25525159, 18212818) -

Autosomal recessive nonsyndromic hearing loss 37 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.93
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121912558; hg19: chr6-76623836;