NM_004999.4:c.647A>T

Variant names:

• chr6-75840678-A-T
• rs121912559
• NM_004999.4:c.647A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004999.4(MYO6):​c.647A>T​(p.Glu216Val) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,606,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 5.96
• Publications: 10 publications found

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]

MYO6 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, ClinGen
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for MYO6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01628673).
• BP6: Variant 6-75840678-A-T is Benign according to our data. Variant chr6-75840678-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8580.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000197 (30/152324) while in subpopulation SAS AF = 0.00601 (29/4826). AF 95% confidence interval is 0.0043. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.647A>T	p.Glu216Val	missense	Exon 8 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.647A>T	p.Glu216Val	missense	Exon 8 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.647A>T	p.Glu216Val	missense	Exon 8 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.647A>T	p.Glu216Val	missense	Exon 8 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.647A>T	p.Glu216Val	missense	Exon 7 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.647A>T	p.Glu216Val	missense	Exon 8 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152206 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: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250648 AF XY: 0.000443

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 276 AN: 1453888 Hom.: 2 Cov.: 29 AF XY: 0.000264 AC XY: 191 AN XY: 723908

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00306 AC: 263 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104848

Other (OTH) AF: 0.000133 AC: 8 AN: 60134

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Autosomal dominant nonsyndromic hearing loss 22 (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.11	B
Vest4		0.82
MutPred		0.79		Loss of disorder (P = 0.0267)
MVP		0.86
MPC		0.30
ClinPred		0.15	T
GERP RS		5.2
gMVP		0.58
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs121912559; hg19: chr6-76550395;