3-46863387-C-A

Position:

• chr3-46863387-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000258.3(MYL3):​c.4G>T​(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N,N,N-trimethylalanine (size 0) in uniprot entity MYL3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3772455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3	c.4G>T	p.Ala2Ser	missense_variant	1/7	ENST00000292327.6	NP_000249.1
MYL3	NM_001406937.1	c.4G>T	p.Ala2Ser	missense_variant	1/6		NP_001393866.1
MYL3	NM_001406938.1	c.4G>T	p.Ala2Ser	missense_variant	3/9		NP_001393867.1
MYL3	NM_001406939.1	c.4G>T	p.Ala2Ser	missense_variant	3/9		NP_001393868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.4G>T	p.Ala2Ser	missense_variant	1/7	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 01, 2019

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces alanine with serine at codon 2 of the MYL3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0024
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.66	.;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.34	N;N;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.020	D;D;.
Sift4G	Benign	0.22	T;T;T
Polyphen		0.56	P;P;.
Vest4		0.38
MutPred		0.19		Loss of glycosylation at P3 (P = 0.0167);Loss of glycosylation at P3 (P = 0.0167);Loss of glycosylation at P3 (P = 0.0167);
MVP		0.78
MPC		0.52
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.062
gMVP		0.42

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

Other links and lift over

dbSNP: rs148310342; hg19: chr3-46904877;