rs201507590

Variant names:

• chr6-75832925-G-A
• rs201507590
• NM_004999.4:c.475G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.475G>A variant in MYO6 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 159 (p.Glu159Lys).​ The filtering allele frequency of this variant is 0.013% for South Asian chromosomes by the Genome Aggregation Database v4 (18/91064 with 95% CI), which meets no population allele frequency criteria (PM2_Supporting, BS1, and BA1 are not met). However, this variant is also present in 0.8% (257/29596) of Ashkenazi Jewish chromosomes, 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). This variant has not been reported in the literature in individuals affected with hearing loss. Therefore, given the lack of contradictory evidence, this variant is classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 01.15.2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA135641/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:4
• Conservation: PhyloP100: 9.60
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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

Our verdict: Benign. The variant received -8 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.475G>A	p.Glu159Lys	missense	Exon 6 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.475G>A	p.Glu159Lys	missense	Exon 6 of 36	NP_001355794.1
	MYO6	NM_001368866.1		c.475G>A	p.Glu159Lys	missense	Exon 6 of 35	NP_001355795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.475G>A	p.Glu159Lys	missense	Exon 6 of 35	ENSP00000358994.3
	MYO6	ENST00000615563.4	TSL:1	c.475G>A	p.Glu159Lys	missense	Exon 5 of 32	ENSP00000478013.1
	MYO6	ENST00000664640.1		c.475G>A	p.Glu159Lys	missense	Exon 6 of 36	ENSP00000499278.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152166 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000466 AC: 117 AN: 251284 AF XY: 0.000479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461088 Hom.: 3 Cov.: 30 AF XY: 0.000286 AC XY: 208 AN XY: 726922

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 229 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111300

Other (OTH) AF: 0.000646 AC: 39 AN: 60368

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152166 Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000699 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:6 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO6: PP3, BS1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 02, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Classified as benign by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000840548.3; PMID: 30311386); This variant is associated with the following publications: (PMID: 30311386)

not specified Uncertain:2

Jan 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu159Lys variant in MYO6 has been identified by our laboratory in 1 indiv idual with hearing loss and in 38/66510 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201507590). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, the clinical significanc e of the p.Glu159Lys variant is uncertain.

Oct 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475G>A (p.E159K) alteration is located in exon 6 (coding exon 5) of the MYO6 gene. This alteration results from a G to A substitution at nucleotide position 475, causing the glutamic acid (E) at amino acid position 159 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Autosomal recessive nonsyndromic hearing loss 37 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Meniere disease Uncertain:1

Jun 03, 2024

Center for Computational Biology & Bioinformatics, University of California, San Diego

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Nonsyndromic genetic hearing loss Benign:1

Jan 15, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.475G>A variant in MYO6 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 159 (p.Glu159Lys). The filtering allele frequency of this variant is 0.013% for South Asian chromosomes by the Genome Aggregation Database v4 (18/91064 with 95% CI), which meets no population allele frequency criteria (PM2_Supporting, BS1, and BA1 are not met). However, this variant is also present in 0.8% (257/29596) of Ashkenazi Jewish chromosomes, 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). This variant has not been reported in the literature in individuals affected with hearing loss. Therefore, given the lack of contradictory evidence, this variant is classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 01.15.2025).

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.074	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.98
MPC		0.29
ClinPred		0.26	T
GERP RS		5.5
gMVP		0.95
Mutation Taster		=6/94	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: rs201507590; hg19: chr6-76542642;