3-123700726-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D914G) has been classified 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

Publications

18 publications found

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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

MYLK-AS1 links:

LOC105369194 (HGNC:):

LOC105369194 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 226759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.2742C>A	p.Asp914Glu	missense_variant	Exon 18 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.2742C>A	p.Asp914Glu	missense_variant	Exon 18 of 34	5	NM_053025.4	ENSP00000353452.3

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

GnomAD2 exomes

AF:

0.102

AC:

25615

AN:

251448

AF XY:

0.105

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 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

African (AFR)

AF:

0.125

AC:

4179

AN:

33480

American (AMR)

AF:

0.0477

AC:

2134

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

618

AN:

26136

East Asian (EAS)

AF:

0.482

AC:

19151

AN:

39698

South Asian (SAS)

AF:

0.242

AC:

20868

AN:

86258

European-Finnish (FIN)

AF:

0.0718

AC:

3837

AN:

53408

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5768

European-Non Finnish (NFE)

AF:

0.0148

AC:

16480

AN:

1112010

Other (OTH)

AF:

0.0776

AC:

4686

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4628

9256

13885

18513

23141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1112

2224

3336

4448

5560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0780

AC:

11869

AN:

152090

Hom.:

1373

Cov.:

AF XY:

0.0847

AC XY:

6296

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.121

AC:

5016

AN:

41474

American (AMR)

AF:

0.0438

AC:

670

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3470

East Asian (EAS)

AF:

0.533

AC:

2749

AN:

5160

South Asian (SAS)

AF:

0.264

AC:

1269

AN:

4800

European-Finnish (FIN)

AF:

0.0828

AC:

877

AN:

10590

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1033

AN:

67992

Other (OTH)

AF:

0.0762

AC:

161

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

470

939

1409

1878

2348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0426

Hom.:

2774

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

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Aug 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aortic aneurysm, familial thoracic 7

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

0.17

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

PromoterAI

0.0066

Neutral

(source)

Varity_R

0.022

gMVP

0.044

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over