NM_000258.3:c.517A>T

Variant names:

• chr3-46858426-T-A
• NM_000258.3:c.517A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000258.3(MYL3):​c.517A>T​(p.Met173Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-46858425-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.20508471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.517A>T	p.Met173Leu	missense_variant	Exon 5 of 7	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.517A>T	p.Met173Leu	missense_variant	Exon 5 of 7	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Benign	0.024
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.64
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.075	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.69	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.52
MutPred		0.46		Loss of glycosylation at K171 (P = 0.0476);Loss of glycosylation at K171 (P = 0.0476);
MVP		0.60
MPC		0.33
ClinPred		0.39	T
GERP RS		3.8
Varity_R		0.38
gMVP		0.80

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: chr3-46899916;