16-46707750-A-C

Variant names:

• chr16-46707750-A-C
• NM_182493.3:c.2414T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182493.3(MYLK3):​c.2414T>G​(p.Val805Gly) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V805A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYLK3 NM_182493.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

MYLK3 (HGNC:29826): (myosin light chain kinase 3) Phosphorylation of cardiac myosin heavy chains (see MYH7B, MIM 609928) and light chains (see MYL2, MIM 160781) by a kinase, such as MYLK3, potentiates the force and rate of cross-bridge recruitment in cardiac myocytes (Chan et al., 2008 [PubMed 18202317]).[supplied by OMIM, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.239835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK3	NM_182493.3	c.2414T>G	p.Val805Gly	missense_variant	Exon 13 of 13	ENST00000394809.9	NP_872299.2
MYLK3	NM_001308301.1	c.1391T>G	p.Val464Gly	missense_variant	Exon 12 of 12		NP_001295230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK3	ENST00000394809.9	c.2414T>G	p.Val805Gly	missense_variant	Exon 13 of 13	1	NM_182493.3	ENSP00000378288.4
MYLK3	ENST00000536476.5	c.1391T>G	p.Val464Gly	missense_variant	Exon 12 of 12	2		ENSP00000439297.1
MYLK3	ENST00000562104.1	n.504T>G		non_coding_transcript_exon_variant	Exon 4 of 4	4
MYLK3	ENST00000565182.5	n.498T>G		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with MYLK3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 805 of the MYLK3 protein (p.Val805Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.00058
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.35	T;T
Polyphen		0.25	B;.
Vest4		0.56
MutPred		0.49		Loss of stability (P = 0.0076);.;
MVP		0.61
MPC		0.68
ClinPred		0.72	D
GERP RS		2.9
Varity_R		0.30
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr16-46741662;