rs75967604

Variant names:

• chr3-123700269-GTTC-G
• rs75967604
• NM_053025.4:c.3196_3198delGAA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.3196_3198delGAA​(p.Glu1066del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,613,884 control chromosomes in the GnomAD database, including 6,375 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (713 hom., cov: 30)
  • Exomes 𝑓: 0.034 (5662 hom.)
• Consequence: MYLK NM_053025.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.76

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]

LOC105369194 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_053025.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-123700269-GTTC-G is Benign according to our data. Variant chr3-123700269-GTTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 194904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700269-GTTC-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.3196_3198delGAA	p.Glu1066del	conservative_inframe_deletion	Exon 18 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.3196_3198delGAA	p.Glu1066del	conservative_inframe_deletion	Exon 18 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5631 AN: 151874 Hom.: 714 Cov.: 30

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0673 AC: 16931 AN: 251436 Hom.: 2812 AF XY: 0.0697 AC XY: 9472 AN XY: 135882

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.506

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0342 AC: 50049 AN: 1461892 Hom.: 5662 AF XY: 0.0373 AC XY: 27101 AN XY: 727246

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.0187

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0547

GnomAD4 genome AF: 0.0370 AC: 5631 AN: 151992 Hom.: 713 Cov.: 30 AF XY: 0.0408 AC XY: 3030 AN XY: 74292

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0193 Hom.: 37

Bravo AF: 0.0378

Asia WGS AF: 0.300 AC: 1039 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 18, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu1066del in exon 18 of MYLK: This variant is not expected to have clinical s ignificance because it has been identified in 50.4% (4361/8650) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs75967604). -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 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. -

Apr 12, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs75967604; hg19: chr3-123419116;