rs4678047

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_053025.4(MYLK):c.1005C>T(p.Thr335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,613,908 control chromosomes in the GnomAD database, including 352,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28815 hom., cov: 32)

Exomes 𝑓: 0.66 ( 323751 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.12

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-123733991-G-A is Benign according to our data. Variant chr3-123733991-G-A is described in ClinVar as [Benign]. Clinvar id is 226753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123733991-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 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.1005C>T	p.Thr335=	synonymous_variant	10/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.1005C>T	p.Thr335=	synonymous_variant	10/34	5	NM_053025.4	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.601

AC:

91243

AN:

151924

Hom.:

28807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.705

Gnomad AMR

AF:

0.697

Gnomad ASJ

AF:

0.645

Gnomad EAS

AF:

0.939

Gnomad SAS

AF:

0.610

Gnomad FIN

AF:

0.630

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.665

Gnomad OTH

AF:

0.645

GnomAD3 exomes

AF:

0.663

AC:

164937

AN:

248802

Hom.:

56027

AF XY:

0.661

AC XY:

89136

AN XY:

134776

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.636

Gnomad EAS exome

AF:

0.942

Gnomad SAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.639

Gnomad NFE exome

AF:

0.664

Gnomad OTH exome

AF:

0.664

GnomAD4 exome

AF:

0.662

AC:

967868

AN:

1461866

Hom.:

323751

Cov.:

AF XY:

0.661

AC XY:

480420

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.387

Gnomad4 AMR exome

AF:

0.703

Gnomad4 ASJ exome

AF:

0.639

Gnomad4 EAS exome

AF:

0.943

Gnomad4 SAS exome

AF:

0.604

Gnomad4 FIN exome

AF:

0.645

Gnomad4 NFE exome

AF:

0.665

Gnomad4 OTH exome

AF:

0.660

GnomAD4 genome

AF:

0.600

AC:

91274

AN:

152042

Hom.:

28815

Cov.:

AF XY:

0.604

AC XY:

44908

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.399

Gnomad4 AMR

AF:

0.697

Gnomad4 ASJ

AF:

0.645

Gnomad4 EAS

AF:

0.940

Gnomad4 SAS

AF:

0.610

Gnomad4 FIN

AF:

0.630

Gnomad4 NFE

AF:

0.665

Gnomad4 OTH

AF:

0.647

Alfa

AF:

0.642

Hom.:

33256

Bravo

AF:

0.600

Asia WGS

AF:

0.738

AC:

2566

AN:

3478

EpiCase

AF:

0.666

EpiControl

AF:

0.665

ClinVar

Significance: Benign

Submissions summary: Benign:14

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	Thr335Thr in exon 10 of MYLK: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 39.2% (1727/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4678047). -
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, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Aortic aneurysm, familial thoracic 7

Benign:4

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

MYLK-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2022

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

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

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.6

DANN

Benign

0.76

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