rs1057524740

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_053025.4(MYLK):c.2009A>T(p.His670Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.93

Variant links:

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]

MYLK links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.2009A>T	p.His670Leu	missense_variant	15/34	ENST00000360304.8
LOC105369194	XR_924417.4 linkuse as main transcript	n.252-3528T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.2009A>T	p.His670Leu	missense_variant	15/34	5	NM_053025.4	P4	Q15746-1
	ENST00000685586.1 linkuse as main transcript	n.612-3528T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251492

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 670 of the MYLK protein (p.His670Leu). This variant is present in population databases (no rsID available, 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: 393012). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2022

The p.H670L variant (also known as c.2009A>T), located in coding exon 12 of the MYLK gene, results from an A to T substitution at nucleotide position 2009. The histidine at codon 670 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.50

.;.;.;T;.;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

.;D;D;D;.;.

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.97

L;.;L;L;.;L

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

D;.;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.068

T;.;T;T;T;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.98

D;D;D;D;D;D

Vest4

0.72

MutPred

0.46

Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);

MVP

0.85

MPC

0.20

ClinPred

0.31

GERP RS

4.3

Varity_R

0.37

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over