rs3796164

chr3-123734214-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.145

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• 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	UniProt
MYLK	NM_053025.4	c.782T>C	p.Val261Ala	missense_variant	10/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.782T>C	p.Val261Ala	missense_variant	10/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23686 AN: 150974 Hom.: 4677 Cov.: 31

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

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.: 47 AF XY: 0.0505 AC XY: 34525 AN XY: 683824

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.: 31 AF XY: 0.158 AC XY: 11692 AN XY: 73812

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: 28

ALSPAC AF: 0.00908 AC: 35

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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. -
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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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 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	Invitae	Feb 01, 2024	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.45
Dann	Benign	0.81
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.097	N
MetaRNN	Benign	0.00018	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs3796164; hg19: chr3-123453061; COSMIC: COSV60609998; COSMIC: COSV60609998;