rs766381045

chr3-123733082-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_053025.4(MYLK):c.1330G>A(p.Glu444Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0650

Genes affected

MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• BP4: Computational evidence support a benign effect (MetaRNN=0.30009538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.1330G>A	p.Glu444Lys	missense_variant	11/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.1330G>A	p.Glu444Lys	missense_variant	11/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249442 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461684 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 22, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 444 of the MYLK protein (p.Glu444Lys). This variant is present in population databases (rs766381045, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 519983). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2016

The p.E444K variant (also known as c.1330G>A), located in coding exon 8 of the MYLK gene, results from a G to A substitution at nucleotide position 1330. The glutamic acid at codon 444 is replaced by lysine, an amino acid with similar properties. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (1/100722). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.096	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.55	P;P;P;P
Vest4		0.18
MutPred		0.55		Gain of methylation at E444 (P = 0.0045);Gain of methylation at E444 (P = 0.0045);Gain of methylation at E444 (P = 0.0045);Gain of methylation at E444 (P = 0.0045);
MVP		0.67
MPC		0.29
ClinPred		0.10	T
GERP RS		1.1
Varity_R		0.31
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs766381045; hg19: chr3-123451929;