rs35912339

chr3-123733989-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_053025.4(MYLK):c.1007C>T(p.Pro336Leu) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,614,150 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P336P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (12 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.72

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 -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• BP4: Computational evidence support a benign effect (MetaRNN=0.006053865).
• BP6: Variant 3-123733989-G-A is Benign according to our data. Variant chr3-123733989-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123733989-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.1007C>T	p.Pro336Leu	missense_variant	10/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.1007C>T	p.Pro336Leu	missense_variant	10/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152162 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00162 AC: 402 AN: 248810 Hom.: 1 AF XY: 0.00191 AC XY: 257 AN XY: 134774

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00389

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00209 AC: 3055 AN: 1461870 Hom.: 12 Cov.: 31 AF XY: 0.00213 AC XY: 1551 AN XY: 727232

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152280 Hom.: 1 Cov.: 33 AF XY: 0.000954 AC XY: 71 AN XY: 74450

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00206 Hom.: 2

Bravo AF: 0.00131

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	MYLK: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2020	Variant summary: MYLK c.1007C>T (p.Pro336Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248810 control chromosomes, including 1 homozygote (gnomAD). The variant was predominantly observed within the South Asian subpopulation (at a frequency of 0.0039), and the European (non-Finnish) subpopulation (at a frequency of 0.0021) in the gnomAD database. These frequencies are approximately 150-fold and 85-fold higher (respectively) than the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1007C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -

Aortic aneurysm, familial thoracic 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2019	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 04, 2023	- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Benign	0.71
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0061	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.90	L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;.;N;N;N;N
REVEL	Benign	0.089
Sift	Uncertain	0.0040	D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.88	P;B;P;P;B;P
Vest4		0.085
MVP		0.74
MPC		0.19
ClinPred		0.035	T
GERP RS		4.4
Varity_R		0.030
gMVP		0.10

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: rs35912339; hg19: chr3-123452836;