NM_004999.4:c.2982G>A

Variant names:

• chr6-75892565-G-A
• rs55905349
• NM_004999.4:c.2982G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004999.4(MYO6):​c.2982G>A​(p.Glu994Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,613,928 control chromosomes in the GnomAD database, including 55 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 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (50 hom.)
• Consequence: MYO6 NM_004999.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.35
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-75892565-G-A is Benign according to our data. Variant chr6-75892565-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45151.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00482 (734/152304) while in subpopulation NFE AF = 0.00801 (545/68000). AF 95% confidence interval is 0.00746. There are 5 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2982G>A	p.Glu994Glu	synonymous	Exon 28 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.2982G>A	p.Glu994Glu	synonymous	Exon 28 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.2982G>A	p.Glu994Glu	synonymous	Exon 28 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.2982G>A	p.Glu994Glu	synonymous	Exon 28 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.2982G>A	p.Glu994Glu	synonymous	Exon 27 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.2982G>A	p.Glu994Glu	synonymous	Exon 28 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152186 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00526 AC: 1323 AN: 251464 AF XY: 0.00542

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00816

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00686 AC: 10034 AN: 1461624 Hom.: 50 Cov.: 31 AF XY: 0.00676 AC XY: 4912 AN XY: 727122

African (AFR) AF: 0.00170 AC: 57 AN: 33470

American (AMR) AF: 0.00356 AC: 159 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86240

European-Finnish (FIN) AF: 0.00588 AC: 314 AN: 53416

Middle Eastern (MID) AF: 0.0126 AC: 70 AN: 5552

European-Non Finnish (NFE) AF: 0.00789 AC: 8772 AN: 1112008

Other (OTH) AF: 0.00595 AC: 359 AN: 60380

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74480

African (AFR) AF: 0.00125 AC: 52 AN: 41580

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00801 AC: 545 AN: 68000

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00708 Hom.: 2

Bravo AF: 0.00463

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
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		1.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.9
Mutation Taster		=100/0	polymorphism

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: rs55905349; hg19: chr6-76602282;