rs1254392

Variant names:

• chr3-123649166-A-G
• rs1254392
• NM_053025.4:c.4317T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):​c.4317T>C​(p.Asp1439Asp) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.28
• Publications: 14 publications found

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]

LOC124909421 (HGNC:):

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.4317T>C	p.Asp1439Asp	synonymous_variant	Exon 25 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.4317T>C	p.Asp1439Asp	synonymous_variant	Exon 25 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37588 AN: 151740 Hom.: 7370 Cov.: 32

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

GnomAD2 exomes AF: 0.232 AC: 58278 AN: 251196 AF XY: 0.218

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 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.: 34 AF XY: 0.138 AC XY: 100021 AN XY: 726860

African (AFR) AF: 0.509 AC: 17022 AN: 33442

American (AMR) AF: 0.410 AC: 18347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4506 AN: 26136

East Asian (EAS) AF: 0.653 AC: 25939 AN: 39700

South Asian (SAS) AF: 0.285 AC: 24557 AN: 86226

European-Finnish (FIN) AF: 0.0971 AC: 5183 AN: 53396

Middle Eastern (MID) AF: 0.203 AC: 1051 AN: 5182

European-Non Finnish (NFE) AF: 0.0816 AC: 90693 AN: 1111982

Other (OTH) AF: 0.170 AC: 10249 AN: 60320

GnomAD4 genome AF: 0.248 AC: 37707 AN: 151858 Hom.: 7412 Cov.: 32 AF XY: 0.253 AC XY: 18758 AN XY: 74212

African (AFR) AF: 0.487 AC: 20122 AN: 41360

American (AMR) AF: 0.308 AC: 4696 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3468

East Asian (EAS) AF: 0.630 AC: 3226 AN: 5118

South Asian (SAS) AF: 0.319 AC: 1529 AN: 4796

European-Finnish (FIN) AF: 0.0896 AC: 948 AN: 10586

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0887 AC: 6025 AN: 67946

Other (OTH) AF: 0.219 AC: 463 AN: 2112

Alfa AF: 0.193 Hom.: 4096

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:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jun 05, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jan 23, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.8
DANN	Benign	0.73
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1254392; hg19: chr3-123368013;