dbSNP rs199474707: MYL3:p.Val156Leu (chr3-46859490-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PM1PM5PP2PP3_ModeratePP5BS2

The NM_000258.3(MYL3):c.466G>T(p.Val156Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V156M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYL3
NM_000258.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6

Conservation

PhyloP100: 7.91

Publications

7 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: 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 4 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000258.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-46859490-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31778.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 3-46859490-C-A is Pathogenic according to our data. Variant chr3-46859490-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177841.

BS2

High AC in GnomAdExome4 at 22 AD,SD gene.

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	UniProt
MYL3	NM_000258.3	MANE Select	c.466G>T	p.Val156Leu	missense	Exon 4 of 7	NP_000249.1	P08590
MYL3	NM_001406937.1		c.466G>T	p.Val156Leu	missense	Exon 4 of 6	NP_001393866.1	P08590
MYL3	NM_001406938.1		c.466G>T	p.Val156Leu	missense	Exon 6 of 9	NP_001393867.1	P08590

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYL3	ENST00000292327.6	TSL:1 MANE Select	c.466G>T	p.Val156Leu	missense	Exon 4 of 7	ENSP00000292327.4	P08590
MYL3	ENST00000395869.5	TSL:1	c.466G>T	p.Val156Leu	missense	Exon 4 of 6	ENSP00000379210.1	P08590
MYL3	ENST00000713934.1		c.598G>T	p.Val200Leu	missense	Exon 4 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251364

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 8 (3)

Cardiomyopathy (2)

not provided (2)

Hypertrophic cardiomyopathy (1)

not specified (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Uncertain

0.18

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.94

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.95

Vest4

0.84

MutPred

0.83

Loss of catalytic residue at V156 (P = 0.0505)

MVP

0.95

MPC

0.79

ClinPred

0.91

GERP RS

4.3

Varity_R

0.66

gMVP

0.78

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over