NM_004999.4:c.475G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

Scores

Clinical Significance

Benign reviewed by expert panel U:6B:4

Conservation

PhyloP100: 9.60

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4 link	c.475G>A	p.Glu159Lys	missense_variant	Exon 6 of 35	ENST00000369977.8	NP_004990.3	Q9UM54-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 link	c.475G>A	p.Glu159Lys	missense_variant	Exon 6 of 35	1	NM_004999.4	ENSP00000358994.3		Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000466

AC:

117

AN:

251284

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135808

show subpopulations

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 SAS exome

AF:

0.000163

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.:

Cov.:

AF XY:

0.000286

AC XY:

208

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00877

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000250

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000866

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 10, 2024

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) -

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;.;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;.;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.074

T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

.;H;H;H;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.9

D;D;D;.;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;.;.

Vest4

0.91

MVP

0.98

MPC

0.29

ClinPred

0.26

GERP RS

5.5

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over