rs3732486

Positions:

Variant summary

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

The NM_053025.4(MYLK):c.2582T>C(p.Leu861Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,612,728 control chromosomes in the GnomAD database, including 12,902 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L861I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 2716 hom., cov: 31)

Exomes 𝑓: 0.055 ( 10186 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.35

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:

LOC105369194 (HGNC:):

LOC105369194 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=1.2800097E-4).

BP6

Variant 3-123700886-A-G is Benign according to our data. Variant chr3-123700886-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700886-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.2582T>C	p.Leu861Pro	missense_variant	18/34	ENST00000360304.8
LOC105369194	XR_924417.4 linkuse as main transcript	n.108-2980A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.2582T>C	p.Leu861Pro	missense_variant	18/34	5	NM_053025.4	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18666

AN:

151820

Hom.:

2698

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0618

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.535

Gnomad SAS

AF:

0.269

Gnomad FIN

AF:

0.0837

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.115

AC:

28763

AN:

249654

Hom.:

4795

AF XY:

0.116

AC XY:

15634

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.0615

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.562

Gnomad SAS exome

AF:

0.252

Gnomad FIN exome

AF:

0.0760

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0733

GnomAD4 exome

AF:

0.0547

AC:

79948

AN:

1460790

Hom.:

10186

Cov.:

AF XY:

0.0595

AC XY:

43229

AN XY:

726770

show subpopulations

Gnomad4 AFR exome

AF:

0.282

Gnomad4 AMR exome

AF:

0.0607

Gnomad4 ASJ exome

AF:

0.0262

Gnomad4 EAS exome

AF:

0.483

Gnomad4 SAS exome

AF:

0.247

Gnomad4 FIN exome

AF:

0.0717

Gnomad4 NFE exome

AF:

0.0154

Gnomad4 OTH exome

AF:

0.0906

GnomAD4 genome

AF:

0.123

AC:

18731

AN:

151938

Hom.:

2716

Cov.:

AF XY:

0.128

AC XY:

9523

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.0616

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.534

Gnomad4 SAS

AF:

0.269

Gnomad4 FIN

AF:

0.0837

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0524

Hom.:

379

Bravo

AF:

0.128

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.260

AC:

1145

ESP6500EA

AF:

0.0179

AC:

154

ExAC

AF:

0.120

AC:

14519

Asia WGS

AF:

0.412

AC:

1430

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Leu861Pro in exon 18 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 26.0% (1145/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs3732486). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2016	- -

Aortic aneurysm, familial thoracic 7

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.18

.;.;.;T;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.13

.;T;T;T;.;.

MetaRNN

Benign

0.00013

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.1

N;.;N;N;.;N

MutationTaster

Benign

0.41

P;P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

2.3

N;.;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.94

T;.;T;T;T;T

Sift4G

Benign

0.91

T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B

Vest4

0.16

MPC

0.26

ClinPred

0.0044

GERP RS

4.8

Varity_R

0.12

gMVP

0.14

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