rs397517053

Variant names:

• chr6-75832920-A-G
• rs397517053
• NM_004999.4:c.470A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004999.4(MYO6):​c.470A>G​(p.Lys157Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.470A>G	p.Lys157Arg	missense_variant	Exon 6 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.470A>G	p.Lys157Arg	missense_variant	Exon 6 of 35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys157Arg variant in MYO6 has been previously reported by our laboratory i n 1 individual with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In addition, this variant is referred to in several func tional studies as the "K157R rigor mutant" and has been used in several function al studies because of its "rigor-like" actin binding, whereby it exhibits an inc reased binding affinity to actin (Arden 2016, Aschenbrenner 2004, Kruppa 2018, M asters 2017, Masters 2017, Waxse 2017), and shows no movement of vesicles along actin filaments (Aschenbrenner 2004). These in vitro functional studies suggest that the variant alters normal protein function, however, these types of assays may not accurately represent biological function. In summary, the clinical signi ficance of the p.Lys157Arg variant is uncertain. ACMG/AMP criteria applied: PM2, PS3_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;H;H;H;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D;D;D;.;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.
Vest4		0.97
MutPred		0.59		Loss of ubiquitination at K157 (P = 0.0107);Loss of ubiquitination at K157 (P = 0.0107);Loss of ubiquitination at K157 (P = 0.0107);Loss of ubiquitination at K157 (P = 0.0107);Loss of ubiquitination at K157 (P = 0.0107);Loss of ubiquitination at K157 (P = 0.0107);
MVP		0.97
MPC		0.21
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.95

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: rs397517053; hg19: chr6-76542637;