rs3796164

Positions:

chr3-123734214-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_053025.4(MYLK):c.782T>C(p.Val261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,537,270 control chromosomes in the GnomAD database, including 14,158 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 4698 hom., cov: 31)

Exomes 𝑓: 0.048 ( 9460 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.145

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.8411875E-4).

BP6

Variant 3-123734214-A-G is Benign according to our data. Variant chr3-123734214-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123734214-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 link	c.782T>C	p.Val261Ala	missense_variant	10/34	ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 link	c.782T>C	p.Val261Ala	missense_variant	10/34	5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23686

AN:

150974

Hom.:

4677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.247

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.116

AC:

21447

AN:

184602

Hom.:

3906

AF XY:

0.107

AC XY:

10540

AN XY:

98406

show subpopulations

Gnomad AFR exome

AF:

0.445

Gnomad AMR exome

AF:

0.0523

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.468

Gnomad SAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0476

AC:

66050

AN:

1386180

Hom.:

9460

Cov.:

AF XY:

0.0505

AC XY:

34525

AN XY:

683824

show subpopulations

Gnomad4 AFR exome

AF:

0.448

Gnomad4 AMR exome

AF:

0.0544

Gnomad4 ASJ exome

AF:

0.0390

Gnomad4 EAS exome

AF:

0.421

Gnomad4 SAS exome

AF:

0.210

Gnomad4 FIN exome

AF:

0.0233

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.0863

GnomAD4 genome

AF:

0.157

AC:

23762

AN:

151090

Hom.:

4698

Cov.:

AF XY:

0.158

AC XY:

11692

AN XY:

73812

show subpopulations

Gnomad4 AFR

AF:

0.435

Gnomad4 AMR

AF:

0.0715

Gnomad4 ASJ

AF:

0.0404

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.247

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.0451

Hom.:

1886

Bravo

AF:

0.173

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.433

AC:

1910

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.111

AC:

13342

Asia WGS

AF:

0.372

AC:

1293

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Val261Ala in exon 10 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 43.3% (1910/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs3796164). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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. -

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	- -

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 29, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.45

DANN

Benign

0.81

DEOGEN2

Benign

0.19

.;.;.;T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.58

.;T;T;T;.;.

MetaRNN

Benign

0.00018

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

L;L;L;L;L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.84

N;.;N;N;N;N

REVEL

Benign

0.064

Sift

Benign

0.16

T;.;T;T;D;T

Sift4G

Benign

0.18

T;T;T;T;T;T

Polyphen

0.0030

B;B;B;B;B;B

Vest4

0.050

MPC

0.50

ClinPred

0.0063

GERP RS

-0.086

Varity_R

0.042

gMVP

0.12

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