rs149530842

Positions:

chr3-123664192-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_053025.4(MYLK):c.3898G>A(p.Ala1300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 0.916

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 Likely_benign. Variant got -4 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=0.012942165).

BP6

Variant 3-123664192-C-T is Benign according to our data. Variant chr3-123664192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 342880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr3-123664192-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.3898G>A	p.Ala1300Thr	missense_variant	23/34	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.3898G>A	p.Ala1300Thr	missense_variant	23/34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000513

AC:

129

AN:

251312

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000261

AC:

382

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000571

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000680

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 7

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	MYLK NM_053026 exon22 p.Ala1231Thr (c.3691G>A): This variant has not been reported in the literature but is present in 0.1% (58/34412) of Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs149530842). This variant is present in ClinVar (Variation ID:342880). This variant threonine (Thr) is present in >10 species including mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MYLK: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 11, 2019	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2019	This alteration is classified as likely 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. -

Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MYLK NM_053026 exon22 p.Ala1231Thr (c.3691G>A): This variant has not been reported in the literature but is present in 0.1% (58/34412) of Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs149530842). This variant is present in ClinVar (Variation ID:342880). This variant threonine (Thr) is present in >10 species including mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

MYLK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;.;.;T;.;T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.063

LIST_S2

Uncertain

0.89

.;D;D;D;.;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.013

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.39

N;.;N;N;.;N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

N;.;N;N;N;N;N

REVEL

Benign

0.044

Sift

Benign

0.43

T;.;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;.

Polyphen

0.0030

B;B;B;B;B;B;.

Vest4

0.31

MVP

0.69

MPC

0.35

ClinPred

0.011

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.28

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