NM_053025.4:c.3558C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_053025.4(MYLK):c.3558C>T(p.Thr1186Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,124 control chromosomes in the GnomAD database, including 405,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 26879 hom., cov: 31)

Exomes 𝑓: 0.70 ( 378592 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.44

Publications

17 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 3-123692742-G-A is Benign according to our data. Variant chr3-123692742-G-A is described in ClinVar as Benign. ClinVar VariationId is 226764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.3558C>T	p.Thr1186Thr	synonymous_variant	Exon 19 of 34	ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.3558C>T	p.Thr1186Thr	synonymous_variant	Exon 19 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.531

AC:

80623

AN:

151868

Hom.:

26882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.808

Gnomad AMR

AF:

0.528

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.0482

Gnomad SAS

AF:

0.450

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.760

Gnomad OTH

AF:

0.570

GnomAD2 exomes

AF:

0.579

AC:

145353

AN:

251122

AF XY:

0.594

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.449

Gnomad ASJ exome

AF:

0.767

Gnomad EAS exome

AF:

0.0439

Gnomad FIN exome

AF:

0.636

Gnomad NFE exome

AF:

0.761

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.699

AC:

1021051

AN:

1460138

Hom.:

378592

Cov.:

AF XY:

0.696

AC XY:

505398

AN XY:

726514

show subpopulations

African (AFR)

AF:

0.148

AC:

4948

AN:

33462

American (AMR)

AF:

0.460

AC:

20579

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

20078

AN:

26118

East Asian (EAS)

AF:

0.0336

AC:

1335

AN:

39690

South Asian (SAS)

AF:

0.487

AC:

41950

AN:

86212

European-Finnish (FIN)

AF:

0.642

AC:

34144

AN:

53190

Middle Eastern (MID)

AF:

0.705

AC:

4043

AN:

5736

European-Non Finnish (NFE)

AF:

0.770

AC:

854773

AN:

1110692

Other (OTH)

AF:

0.650

AC:

39201

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14422

28844

43266

57688

72110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19912

39824

59736

79648

99560

<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:

0.530

AC:

80610

AN:

151986

Hom.:

26879

Cov.:

AF XY:

0.521

AC XY:

38722

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.169

AC:

7013

AN:

41470

American (AMR)

AF:

0.528

AC:

8059

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2656

AN:

3472

East Asian (EAS)

AF:

0.0479

AC:

248

AN:

5174

South Asian (SAS)

AF:

0.451

AC:

2160

AN:

4794

European-Finnish (FIN)

AF:

0.634

AC:

6685

AN:

10552

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.760

AC:

51654

AN:

67930

Other (OTH)

AF:

0.563

AC:

1190

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1389

2779

4168

5558

6947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.681

Hom.:

106957

Bravo

AF:

0.508

Asia WGS

AF:

0.254

AC:

890

AN:

3478

EpiCase

AF:

0.769

EpiControl

AF:

0.768

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr1186Thr in exon 19 of MYLK: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 23.7% (2042/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs40305). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 7

Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 12, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: This c.3558C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change not very close to exon-intron boundary. 5/5 in silico programs via Alamut predict that this variant does not affect normal splicing. This variant was found in 70165/121320 control chromosomes from ExAC at a frequency of 0.5783465, which is more than 46266 times greater than the maximal expected frequency of a pathogenic allele (0.0000125) in this gene. This shows that this variant is a very common benign polymorphism. Taken together, this variant has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Dec 30, 2014

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. -

Megacystis, microcolon, hypoperistalsis syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.9

(source)

DANN

Benign

0.88

PhyloP100

-1.4

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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