rs1254392

Positions:

chr3-123649166-A-G

Variant summary

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

The NM_053025.4(MYLK):c.4317T>C(p.Asp1439=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,966 control chromosomes in the GnomAD database, including 33,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 7412 hom., cov: 32)

Exomes 𝑓: 0.14 ( 26414 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.28

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:

LOC124909421 (HGNC:):

LOC124909421 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=-0.55).

BP6

Variant 3-123649166-A-G is Benign according to our data. Variant chr3-123649166-A-G is described in ClinVar as [Benign]. Clinvar id is 226770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123649166-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 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.4317T>C	p.Asp1439=	synonymous_variant	25/34	ENST00000360304.8	NP_444253.3
LOC124909421	XR_007096038.1 linkuse as main transcript	n.106A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.4317T>C	p.Asp1439=	synonymous_variant	25/34	5	NM_053025.4	ENSP00000353452	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37588

AN:

151740

Hom.:

7370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.0896

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0887

Gnomad OTH

AF:

0.215

GnomAD3 exomes

AF:

0.232

AC:

58278

AN:

251196

Hom.:

10998

AF XY:

0.218

AC XY:

29633

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.495

Gnomad AMR exome

AF:

0.425

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.617

Gnomad SAS exome

AF:

0.290

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.0905

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.135

AC:

197547

AN:

1461108

Hom.:

26414

Cov.:

AF XY:

0.138

AC XY:

100021

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.509

Gnomad4 AMR exome

AF:

0.410

Gnomad4 ASJ exome

AF:

0.172

Gnomad4 EAS exome

AF:

0.653

Gnomad4 SAS exome

AF:

0.285

Gnomad4 FIN exome

AF:

0.0971

Gnomad4 NFE exome

AF:

0.0816

Gnomad4 OTH exome

AF:

0.170

GnomAD4 genome

AF:

0.248

AC:

37707

AN:

151858

Hom.:

7412

Cov.:

AF XY:

0.253

AC XY:

18758

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.487

Gnomad4 AMR

AF:

0.308

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.630

Gnomad4 SAS

AF:

0.319

Gnomad4 FIN

AF:

0.0896

Gnomad4 NFE

AF:

0.0887

Gnomad4 OTH

AF:

0.219

Alfa

AF:

0.160

Hom.:

1789

Bravo

AF:

0.276

Asia WGS

AF:

0.466

AC:

1619

AN:

3478

EpiCase

AF:

0.0921

EpiControl

AF:

0.0948

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2014	p.Asp1439Asp in exon 25 of MYLK: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 9% (809/8600) of European American chromosomes and 48% (2112/4406) of African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs1254392). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.8

DANN

Benign

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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