3-123700726-G-T

Position:

chr3-123700726-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_053025.4(MYLK):c.2742C>A(p.Asp914Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 1,613,966 control chromosomes in the GnomAD database, including 10,207 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 1373 hom., cov: 31)

Exomes 𝑓: 0.049 ( 8834 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.167

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 Benign. Variant got -19 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.

BP4

Computational evidence support a benign effect (MetaRNN=1.6468763E-4).

BP6

Variant 3-123700726-G-T is Benign according to our data. Variant chr3-123700726-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700726-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.2742C>A	p.Asp914Glu	missense_variant	18/34	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.2742C>A	p.Asp914Glu	missense_variant	18/34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11825

AN:

151972

Hom.:

1362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0440

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.0828

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0679

GnomAD3 exomes

AF:

0.102

AC:

25615

AN:

251448

Hom.:

4219

AF XY:

0.105

AC XY:

14265

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.0498

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.561

Gnomad SAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.0761

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0675

GnomAD4 exome

AF:

0.0494

AC:

72157

AN:

1461876

Hom.:

8834

Cov.:

AF XY:

0.0546

AC XY:

39683

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.0477

Gnomad4 ASJ exome

AF:

0.0236

Gnomad4 EAS exome

AF:

0.482

Gnomad4 SAS exome

AF:

0.242

Gnomad4 FIN exome

AF:

0.0718

Gnomad4 NFE exome

AF:

0.0148

Gnomad4 OTH exome

AF:

0.0776

GnomAD4 genome

AF:

0.0780

AC:

11869

AN:

152090

Hom.:

1373

Cov.:

AF XY:

0.0847

AC XY:

6296

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.0438

Gnomad4 ASJ

AF:

0.0239

Gnomad4 EAS

AF:

0.533

Gnomad4 SAS

AF:

0.264

Gnomad4 FIN

AF:

0.0828

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.0762

Alfa

AF:

0.0355

Hom.:

980

Bravo

AF:

0.0772

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.114

AC:

504

ESP6500EA

AF:

0.0172

AC:

148

ExAC

AF:

0.104

AC:

12577

Asia WGS

AF:

0.401

AC:

1392

AN:

3478

EpiCase

AF:

0.0140

EpiControl

AF:

0.0140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Asp914Glu in exon 18 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 11.4% (504/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs3732487). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aortic aneurysm, familial thoracic 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.25

.;.;.;T;.;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.72

.;T;T;T;.;.

MetaRNN

Benign

0.00016

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.0

L;.;L;L;.;L

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;.;N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.34

T;.;T;T;T;T

Sift4G

Benign

0.45

T;T;T;T;T;T

Polyphen

0.0050

B;B;B;B;B;B

Vest4

0.060

MutPred

0.23

Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);

MPC

0.15

ClinPred

0.014

GERP RS

-0.82

Varity_R

0.022

gMVP

0.044

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