Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM2PP2BP4_StrongBP6

The NM_000258.3(MYL3):c.36T>G(p.Asp12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D12G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.11

Publications

0 publications found

Variant links:

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

MYL3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 8
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_000258.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.75572 (below the threshold of 3.09). Trascript score misZ: 1.3243 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy 8.

BP4

Computational evidence support a benign effect (MetaRNN=0.043186277).

BP6

Variant 3-46863355-A-C is Benign according to our data. Variant chr3-46863355-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 921129.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYL3	NM_000258.3	MANE Select	c.36T>G	p.Asp12Glu	missense	Exon 1 of 7	NP_000249.1
MYL3	NM_001406937.1		c.36T>G	p.Asp12Glu	missense	Exon 1 of 6	NP_001393866.1
MYL3	NM_001406938.1		c.36T>G	p.Asp12Glu	missense	Exon 3 of 9	NP_001393867.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYL3	ENST00000292327.6	TSL:1 MANE Select	c.36T>G	p.Asp12Glu	missense	Exon 1 of 7	ENSP00000292327.4
MYL3	ENST00000395869.5	TSL:1	c.36T>G	p.Asp12Glu	missense	Exon 1 of 6	ENSP00000379210.1
MYL3	ENST00000713934.1		c.36T>G	p.Asp12Glu	missense	Exon 1 of 7	ENSP00000519231.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251100

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

CardioboostCm

Benign

0.0056

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0010

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.27

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.61

PhyloP100

-5.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.12

REVEL

Uncertain

0.31

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.037

MutPred

0.15

Loss of glycosylation at P8 (P = 0.0162)

MVP

0.44

MPC

0.32

ClinPred

0.033

GERP RS

-7.2

PromoterAI

0.026

Neutral

(source)

Varity_R

0.027

gMVP

0.099

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over