rs9840993

Positions:

• chr3-123739046-G-A
• chr3-123739046-G-C
• chr3-123739046-G-T

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.439C>T​(p.Pro147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,613,666 control chromosomes in the GnomAD database, including 762,095 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (61300 hom., cov: 31)
  • Exomes 𝑓: 0.98 (700795 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.16

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=6.1008615E-7).
• BP6: Variant 3-123739046-G-A is Benign according to our data. Variant chr3-123739046-G-A is described in ClinVar as [Benign]. Clinvar id is 198606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123739046-G-A is described in Lovd as [Benign]. Variant chr3-123739046-G-A is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.439C>T	p.Pro147Ser	missense_variant	7/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.439C>T	p.Pro147Ser	missense_variant	7/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134504 AN: 151972 Hom.: 61294 Cov.: 31

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.943

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.922

Gnomad FIN AF: 0.962

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.995

Gnomad OTH AF: 0.905

GnomAD3 exomes AF: 0.948 AC: 237916 AN: 250870 Hom.: 113805 AF XY: 0.954 AC XY: 129366 AN XY: 135572

Gnomad AFR exome AF: 0.632

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.966

Gnomad EAS exome AF: 0.937

Gnomad SAS exome AF: 0.926

Gnomad FIN exome AF: 0.969

Gnomad NFE exome AF: 0.994

Gnomad OTH exome AF: 0.966

GnomAD4 exome AF: 0.977 AC: 1428507 AN: 1461576 Hom.: 700795 Cov.: 60 AF XY: 0.977 AC XY: 710333 AN XY: 727040

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.963

Gnomad4 EAS exome AF: 0.938

Gnomad4 SAS exome AF: 0.928

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.996

Gnomad4 OTH exome AF: 0.956

GnomAD4 genome AF: 0.885 AC: 134547 AN: 152090 Hom.: 61300 Cov.: 31 AF XY: 0.886 AC XY: 65882 AN XY: 74328

Gnomad4 AFR AF: 0.641

Gnomad4 AMR AF: 0.943

Gnomad4 ASJ AF: 0.966

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.922

Gnomad4 FIN AF: 0.962

Gnomad4 NFE AF: 0.995

Gnomad4 OTH AF: 0.903

Alfa AF: 0.971 Hom.: 121198

Bravo AF: 0.872

TwinsUK AF: 0.996 AC: 3694

ALSPAC AF: 0.997 AC: 3844

ESP6500AA AF: 0.637 AC: 2808

ESP6500EA AF: 0.993 AC: 8539

ExAC AF: 0.944 AC: 114556

Asia WGS AF: 0.890 AC: 3094 AN: 3478

EpiCase AF: 0.993

EpiControl AF: 0.993

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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	Genome Diagnostics Laboratory, Amsterdam University 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	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2014	This is a RefSeq error. The reference base (c.439C) is the minor allele. This al lele (C) has been identified in 0.7% (61/8600) of European American chromosomes and 36% (1598/4406) of African American chromosomes by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs9840993) and thus meets cr iteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aortic aneurysm, familial thoracic 7 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2016	Variant summary: This c.439C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant was found in 114076/120782 control chromosomes from ExAC at a frequency of 0.9444785, which is more than 75557 times greater than the maximal expected frequency of a pathogenic allele (0.0000125) in this gene. This proves that this variant is a very common polymorphism. One clinical lab (via ClinVar) has classified this variant as benign. Taken together, this variant has been classified as Benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 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. -

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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.87
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.85
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	6.1e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L;L;L;L;L;L
MutationTaster	Benign	0.99	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;.;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.29	T;.;T;T;T;T
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		0.095	B;B;B;B;B;B
Vest4		0.13
MPC		0.16
ClinPred		0.0077	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9840993; hg19: chr3-123457893;