6-75835938-G-T

Position:

• chr6-75835938-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004999.4(MYO6):​c.535G>T​(p.Asp179Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D179G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.41

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 6-75835938-G-T is Pathogenic according to our data. Variant chr6-75835938-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517508.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.535G>T	p.Asp179Tyr	missense_variant	7/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.535G>T	p.Asp179Tyr	missense_variant	7/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Aug 26, 2017

The p.Asp179Tyr variant in MYO6 has not been previously reported in individuals with hearing loss and was absent from large population studies. The aspartic aci d (Asp) residue at position 179 is highly conserved across species including mic e, and the same variant (p.Asp179Tyr) was identified in a dominant mouse mutant (Tailchaser) displaying hearing and vestibular dysfunction (Hertzano 2008). Scan ning electron microscopy (SEM) of cochlea from both heterozygous and homozygous Tailchaser mice showed structural defects in the stereocilia, and severely disor ganized hair bundles compared to wild-type mice. In addition, an in vitro functi onal assay revealed that the mutant p.Asp179Tyr protein localized to endocytic v esicles but failed to transport the vesicles to the early endosome (Hertzano 200 8). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic based on the functional evidence and absence in the general population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;D;.;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.91
MutPred		0.60		Gain of phosphorylation at D179 (P = 0.0265);Gain of phosphorylation at D179 (P = 0.0265);Gain of phosphorylation at D179 (P = 0.0265);Gain of phosphorylation at D179 (P = 0.0265);Gain of phosphorylation at D179 (P = 0.0265);Gain of phosphorylation at D179 (P = 0.0265);
MVP		0.97
MPC		0.32
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.74

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: rs1554205683; hg19: chr6-76545655;