rs9840993

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.439C>T(p.Pro147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,613,666 control chromosomes in the GnomAD database, including 762,095 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 Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 61300 hom., cov: 31)

Exomes 𝑓: 0.98 ( 700795 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.16

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:

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=6.1008615E-7).

BP6

Variant 3-123739046-G-A is Benign according to our data. Variant chr3-123739046-G-A is described in ClinVar as [Benign]. Clinvar id is 198606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123739046-G-A is described in Lovd as [Benign]. Variant chr3-123739046-G-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.988 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.439C>T	p.Pro147Ser	missense_variant	7/34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.439C>T	p.Pro147Ser	missense_variant	7/34	5	NM_053025.4	ENSP00000353452	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.885

AC:

134504

AN:

151972

Hom.:

61294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.943

Gnomad ASJ

AF:

0.966

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.962

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.995

Gnomad OTH

AF:

0.905

GnomAD3 exomes

AF:

0.948

AC:

237916

AN:

250870

Hom.:

113805

AF XY:

0.954

AC XY:

129366

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.632

Gnomad AMR exome

AF:

0.951

Gnomad ASJ exome

AF:

0.966

Gnomad EAS exome

AF:

0.937

Gnomad SAS exome

AF:

0.926

Gnomad FIN exome

AF:

0.969

Gnomad NFE exome

AF:

0.994

Gnomad OTH exome

AF:

0.966

GnomAD4 exome

AF:

0.977

AC:

1428507

AN:

1461576

Hom.:

700795

Cov.:

AF XY:

0.977

AC XY:

710333

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.624

Gnomad4 AMR exome

AF:

0.949

Gnomad4 ASJ exome

AF:

0.963

Gnomad4 EAS exome

AF:

0.938

Gnomad4 SAS exome

AF:

0.928

Gnomad4 FIN exome

AF:

0.973

Gnomad4 NFE exome

AF:

0.996

Gnomad4 OTH exome

AF:

0.956

GnomAD4 genome

AF:

0.885

AC:

134547

AN:

152090

Hom.:

61300

Cov.:

AF XY:

0.886

AC XY:

65882

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.641

Gnomad4 AMR

AF:

0.943

Gnomad4 ASJ

AF:

0.966

Gnomad4 EAS

AF:

0.938

Gnomad4 SAS

AF:

0.922

Gnomad4 FIN

AF:

0.962

Gnomad4 NFE

AF:

0.995

Gnomad4 OTH

AF:

0.903

Alfa

AF:

0.971

Hom.:

121198

Bravo

AF:

0.872

TwinsUK

AF:

0.996

AC:

3694

ALSPAC

AF:

0.997

AC:

3844

ESP6500AA

AF:

0.637

AC:

2808

ESP6500EA

AF:

0.993

AC:

8539

ExAC

AF:

0.944

AC:

114556

Asia WGS

AF:

0.890

AC:

3094

AN:

3478

EpiCase

AF:

0.993

EpiControl

AF:

0.993

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2014	This is a RefSeq error. The reference base (c.439C) is the minor allele. This al lele (C) has been identified in 0.7% (61/8600) of European American chromosomes and 36% (1598/4406) of African American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs9840993) and thus meets cr iteria to be classified as benign. -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Aortic aneurysm, familial thoracic 7

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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	Mar 06, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2016	Variant summary: This c.439C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant was found in 114076/120782 control chromosomes from ExAC at a frequency of 0.9444785, which is more than 75557 times greater than the maximal expected frequency of a pathogenic allele (0.0000125) in this gene. This proves that this variant is a very common polymorphism. One clinical lab (via ClinVar) has classified this variant as benign. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 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. -

Megacystis, microcolon, hypoperistalsis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.29

.;.;.;T;.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.85

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.75

.;T;T;T;.;.

MetaRNN

Benign

6.1e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;L;L;L;L;L

MutationTaster

Benign

0.99

P;P;P;P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;.;N;N;N;N

REVEL

Benign

0.088

Sift

Benign

0.29

T;.;T;T;T;T

Sift4G

Uncertain

0.0090

D;D;D;D;D;D

Polyphen

0.095

B;B;B;B;B;B

Vest4

0.13

MPC

0.16

ClinPred

0.0077

GERP RS

1.3

Varity_R

0.037

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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