3-46863387-C-T

Variant names:

• chr3-46863387-C-T
• NM_000258.3:c.4G>A

Variant summary

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

The NM_000258.3(MYL3):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,904 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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 rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 7	ENST00000292327.6	NP_000249.1
MYL3	NM_001406937.1	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 6		NP_001393866.1
MYL3	NM_001406938.1	c.4G>A	p.Ala2Thr	missense_variant	Exon 3 of 9		NP_001393867.1
MYL3	NM_001406939.1	c.4G>A	p.Ala2Thr	missense_variant	Exon 3 of 9		NP_001393868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 7	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460904 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726772

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostCm	Benign	0.0015
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	.;T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.53	N;N;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D;D;.
Sift4G	Benign	0.077	T;T;T
Polyphen		0.72	P;P;.
Vest4		0.24
MutPred		0.17		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		0.81
MPC		0.54
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.065
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46904877;