chr3-123657207-G-A

Position:

chr3-123657207-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_053025.4(MYLK):c.4207C>T(p.Arg1403Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,036 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.88

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:

MYLK (HGNC:):

MYLK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.4207C>T	p.Arg1403Cys	missense_variant	24/34	ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.4207C>T	p.Arg1403Cys	missense_variant	24/34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251414

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727246

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Aug 28, 2021

This sequence change replaces arginine with cysteine at codon 1403 of the MYLK protein (p.Arg1403Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs748559781, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Mar 20, 2023

The p.R1403C variant (also known as c.4207C>T), located in coding exon 21 of the MYLK gene, results from a C to T substitution at nucleotide position 4207. The arginine at codon 1403 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Arnaud P et al. Genet Med, 2019 Sep;21:2015-2024). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Oct 19, 2021

Has been reported in association with TAAD in published literature (Arnaud et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30739908) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

.;.;.;D;.;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D;.;.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

4.4

H;.;H;H;.;H;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.2

D;.;D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.

Polyphen

1.0

D;D;D;D;D;D;.

Vest4

0.93

MutPred

0.76

Loss of ubiquitination at K1401 (P = 0.0801);.;Loss of ubiquitination at K1401 (P = 0.0801);Loss of ubiquitination at K1401 (P = 0.0801);.;Loss of ubiquitination at K1401 (P = 0.0801);.;

MVP

0.93

MPC

0.64

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.87

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

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