rs145564837

Variant names:

• chr6-75848478-C-T
• rs145564837
• NM_004999.4:c.1025C>T
• MYO6 p.Ala342Val

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BA1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ala342Val variant in the MYO6 gene is 0.21% for European (non-Finnish) chromosomes by gnomAD (304/129090 with 95% CI), and one homozygous European (Finnish) individual, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss variants (BA1). The REVEL computational prediction analysis tool produced a score of 0.905, however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, the HL EP classified this variant as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135587/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:11
• Conservation: PhyloP100: 7.54
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -7 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1025C>T	p.Ala342Val	missense	Exon 11 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.1025C>T	p.Ala342Val	missense	Exon 11 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.1025C>T	p.Ala342Val	missense	Exon 11 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.1025C>T	p.Ala342Val	missense	Exon 11 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.1025C>T	p.Ala342Val	missense	Exon 10 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.1025C>T	p.Ala342Val	missense	Exon 11 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00133 AC: 334 AN: 251308 AF XY: 0.00137

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00153 AC: 2231 AN: 1461642 Hom.: 2 Cov.: 31 AF XY: 0.00146 AC XY: 1065 AN XY: 727122

African (AFR) AF: 0.000269 AC: 9 AN: 33462

American (AMR) AF: 0.000201 AC: 9 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00245 AC: 131 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00179 AC: 1990 AN: 1111844

Other (OTH) AF: 0.00131 AC: 79 AN: 60386

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74442

African (AFR) AF: 0.000289 AC: 12 AN: 41566

American (AMR) AF: 0.000393 AC: 6 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37 (1)
-	-	1	MYO6-related disorder (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
gMVP		0.88
Mutation Taster		=16/84	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145564837;

hg19: chr6-76558195;