rs757840030

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_002471.4(MYH6):c.3988G>A(p.Ala1330Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000368 in 1,275,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 5.95

Publications

0 publications found

Variant links:

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 Gene-Disease associations (from GenCC):

MYH-6 related congenital heart defects
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Keppen-Lubinsky syndrome
Inheritance: AD Classification: MODERATE Submitted by: Illumina
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atrial septal defect 3
Inheritance: AD Classification: LIMITED Submitted by: G2P
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104382634).

BP6

Variant 14-23389046-C-T is Benign according to our data. Variant chr14-23389046-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191714.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000606 (8/131976) while in subpopulation EAS AF = 0.00141 (6/4252). AF 95% confidence interval is 0.000614. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002471.4. 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
	MYH6	NM_002471.4	MANE Select	c.3988G>A	p.Ala1330Thr	missense	Exon 29 of 39	NP_002462.2	P13533

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH6	ENST00000405093.9	TSL:5 MANE Select	c.3988G>A	p.Ala1330Thr	missense	Exon 29 of 39	ENSP00000386041.3	P13533
MYH6	ENST00000968262.1		c.4021G>A	p.Ala1341Thr	missense	Exon 29 of 39	ENSP00000638321.1
MYH6	ENST00000968257.1		c.3988G>A	p.Ala1330Thr	missense	Exon 29 of 39	ENSP00000638316.1

Frequencies

GnomAD3 genomes

AF:

0.0000606

AC:

AN:

131976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000660

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00141

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000166

AC:

AN:

217380

AF XY:

0.000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000301

Gnomad OTH exome

AF:

0.000189

GnomAD4 exome

AF:

0.0000341

AC:

AN:

1143498

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

572572

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31788

American (AMR)

AF:

0.000127

AC:

AN:

39420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22220

East Asian (EAS)

AF:

0.000572

AC:

AN:

29718

South Asian (SAS)

AF:

0.00

AC:

AN:

78478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39986

Middle Eastern (MID)

AF:

0.000211

AC:

AN:

4736

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

848922

Other (OTH)

AF:

0.000104

AC:

AN:

48230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000606

AC:

AN:

131976

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

64168

show subpopulations

African (AFR)

AF:

0.0000660

AC:

AN:

30308

American (AMR)

AF:

0.00

AC:

AN:

13982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3284

East Asian (EAS)

AF:

0.00141

AC:

AN:

4252

South Asian (SAS)

AF:

0.00

AC:

AN:

3848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64390

Other (OTH)

AF:

0.00

AC:

AN:

1884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000699

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Congestive heart failure (1)

Hypertrophic cardiomyopathy 14 (1)

MYH6-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Benign

0.054

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.10

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.1

PhyloP100

5.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.42

Sift

Uncertain

0.014

Sift4G

Benign

0.19

Polyphen

0.083

Vest4

0.66

MutPred

0.32

Gain of phosphorylation at A1330 (P = 0.0233)

MVP

0.73

MPC

0.30

ClinPred

0.13

GERP RS

3.8

Varity_R

0.28

gMVP

0.22

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over