rs374662467

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_053025.4(MYLK):c.5132C>T(p.Thr1711Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1711R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.11

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38888866).

BP6

Variant 3-123626924-G-A is Benign according to our data. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734. Variant chr3-123626924-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 471734.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.5132C>T	p.Thr1711Met	missense_variant	Exon 31 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.5132C>T	p.Thr1711Met	missense_variant	Exon 31 of 34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251464

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111984

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000657

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000282

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 27, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYLK: BP4 -

Aortic aneurysm, familial thoracic 7

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1711 of the MYLK protein (p.Thr1711Met). This variant is present in population databases (rs374662467, gnomAD 0.008%). 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: 471734). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. 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

Dec 18, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T1711M variant (also known as c.5132C>T), located in coding exon 28 of the MYLK gene, results from a C to T substitution at nucleotide position 5132. The threonine at codon 1711 is replaced by methionine, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;.;.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D;D;D;.;.

M_CAP

Benign

0.031

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.57

.;.;.;N;.;N

PhyloP100

5.1

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.9

D;.;D;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0070

D;.;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.54

MutPred

0.47

.;.;.;Gain of catalytic residue at T1711 (P = 0.0077);.;Gain of catalytic residue at T1711 (P = 0.0077);

MVP

0.93

MPC

0.86

ClinPred

0.61

GERP RS

5.2

Varity_R

0.18

gMVP

0.45

Mutation Taster

=62/38

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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