rs41269323

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004999.4(MYO6):c.3667G>A(p.Asp1223Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,614,072 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0080 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 98 hom. )

Consequence

MYO6
NM_004999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 9.57

Publications

23 publications found

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 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

MYO6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.010249913).

BP6

Variant 6-75914821-G-A is Benign according to our data. Variant chr6-75914821-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45159.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00803 (1223/152302) while in subpopulation NFE AF = 0.0102 (693/68024). AF 95% confidence interval is 0.00956. There are 16 homozygotes in GnomAd4. There are 610 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4 link	c.3667G>A	p.Asp1223Asn	missense_variant	Exon 35 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.3667G>A	p.Asp1223Asn	missense_variant	Exon 35 of 35	1	NM_004999.4	ENSP00000358994.3		Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.00804

AC:

1224

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.0104

AC:

2622

AN:

251390

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.0449

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00970

AC:

14175

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

7066

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

33472

American (AMR)

AF:

0.00662

AC:

296

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

1136

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00710

AC:

612

AN:

86244

European-Finnish (FIN)

AF:

0.0103

AC:

549

AN:

53418

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5766

European-Non Finnish (NFE)

AF:

0.00961

AC:

10683

AN:

1111924

Other (OTH)

AF:

0.0121

AC:

728

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

732

1463

2195

2926

3658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00803

AC:

1223

AN:

152302

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41570

American (AMR)

AF:

0.00562

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0136

AC:

144

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

693

AN:

68024

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00746

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00995

AC:

1208

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asp1223Asn in exon 35 of MYO6: This variant is not expected to have clinical sig nificance because it was identified in 0.8% (44/5483 chromosomes) of a broad pop ulation (dbSNP rs41269323) and computational analyses do not predict a high like lihood of impact to the protein. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29224747) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO6: PP3, BS1, BS2 -

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. -

Autosomal dominant nonsyndromic hearing loss 22

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.;.;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Pathogenic

0.84

PhyloP100

9.6

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.5

.;D;D;.;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

.;D;D;.;T;.

Sift4G

Benign

0.062

T;T;T;T;T;T

Polyphen

1.0

.;D;D;D;.;.

Vest4

0.60

MPC

0.91

ClinPred

0.023

GERP RS

6.1

gMVP

0.82

Mutation Taster

=12/88

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over