6-75848404-T-G

Variant names:

• chr6-75848404-T-G
• rs397517055
• NM_004999.4:c.951T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004999.4(MYO6):​c.951T>G​(p.Phe317Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F317F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231

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, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.951T>G	p.Phe317Leu	missense_variant	Exon 11 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.951T>G	p.Phe317Leu	missense_variant	Exon 11 of 35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	.;M;M;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D;D;D;.;D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D;D;D;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.82, 0.95	.;P;P;P;.;.
Vest4		0.97
MutPred		0.85		Gain of disorder (P = 0.0803);Gain of disorder (P = 0.0803);Gain of disorder (P = 0.0803);Gain of disorder (P = 0.0803);Gain of disorder (P = 0.0803);Gain of disorder (P = 0.0803);
MVP		0.75
MPC		0.30
ClinPred		0.97	D
GERP RS		1.6
gMVP		0.86

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: rs397517055; hg19: chr6-76558121;