3-46858255-T-C

Position:

• chr3-46858255-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000258.3(MYL3):​c.577A>G​(p.Met193Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.76

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 4 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3	c.577A>G	p.Met193Val	missense_variant	6/7	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.577A>G	p.Met193Val	missense_variant	6/7	1	NM_000258.3	ENSP00000292327	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 23, 2023

This missense variant replaces methionine with valine at codon 193 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYL3-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces methionine with valine at codon 193 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 is rare in the general population and has been identified in 0/277264 chromosomes 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	Uncertain	0.44
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.066	T;T
Polyphen		0.88	P;P
Vest4		0.59
MutPred		0.36		Loss of glycosylation at S195 (P = 0.075);Loss of glycosylation at S195 (P = 0.075);
MVP		0.75
MPC		0.64
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.52
gMVP		0.65

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: rs1701951996; hg19: chr3-46899745;