chr3-123700935-G-A

Position:

chr3-123700935-G-A

Variant summary

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

The NM_053025.4(MYLK):c.2533C>T(p.Arg845Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,056 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 62 hom., cov: 30)

Exomes 𝑓: 0.012 ( 586 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0490

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 (HGNC:):

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=0.0014624298).

BP6

Variant 3-123700935-G-A is Benign according to our data. Variant chr3-123700935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700935-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0789 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.2533C>T	p.Arg845Cys	missense_variant	18/34	ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.2533C>T	p.Arg845Cys	missense_variant	18/34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2477

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.0484

Gnomad SAS

AF:

0.0856

Gnomad FIN

AF:

0.0660

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0270

AC:

6650

AN:

246212

Hom.:

240

AF XY:

0.0293

AC XY:

3925

AN XY:

134066

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0297

Gnomad ASJ exome

AF:

0.00331

Gnomad EAS exome

AF:

0.0505

Gnomad SAS exome

AF:

0.0888

Gnomad FIN exome

AF:

0.0582

Gnomad NFE exome

AF:

0.00375

Gnomad OTH exome

AF:

0.0190

GnomAD4 exome

AF:

0.0117

AC:

17118

AN:

1458928

Hom.:

586

Cov.:

AF XY:

0.0140

AC XY:

10192

AN XY:

725962

show subpopulations

Gnomad4 AFR exome

AF:

0.0157

Gnomad4 AMR exome

AF:

0.0269

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.0398

Gnomad4 SAS exome

AF:

0.0871

Gnomad4 FIN exome

AF:

0.0535

Gnomad4 NFE exome

AF:

0.00225

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0163

AC:

2484

AN:

152128

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1490

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0164

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.0481

Gnomad4 SAS

AF:

0.0857

Gnomad4 FIN

AF:

0.0660

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00619

Hom.:

Bravo

AF:

0.0117

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.0265

AC:

3213

Asia WGS

AF:

0.0750

AC:

259

AN:

3476

EpiCase

AF:

0.00218

EpiControl

AF:

0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2020	Variant summary: MYLK c.2533C>T (p.Arg845Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 246212 control chromosomes in the gnomAD database, including 240 homozygotes. The observed variant frequency is approximately 1080-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2533C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Arg845Cys in exon 18 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 1.4% (61/4402) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs3732485). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2016	- -

Aortic aneurysm, familial thoracic 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 01, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Aortic aneurysm, familial thoracic 6

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.23

.;.;.;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.78

.;T;T;T;.;.

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;N;N;.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.58

N;.;N;N;N;N

REVEL

Benign

0.062

Sift

Benign

0.25

T;.;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.021

B;B;B;B;B;B

Vest4

0.083

MPC

0.22

ClinPred

0.0016

GERP RS

1.3

Varity_R

0.048

gMVP

0.21

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