3-123649196-TG-TGG

Variant names:

• chr3-123649196-T-TG
• rs41431347
• NM_053025.4:c.4289-3dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.4289-3dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,605,586 control chromosomes in the GnomAD database, including 1,233 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (98 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1135 hom.)
• Consequence: MYLK NM_053025.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.798
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 3-123649196-T-TG is Benign according to our data. Variant chr3-123649196-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.4289-3dupC		splice_region_variant, intron_variant	Intron 24 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.4289-3_4289-2insC		splice_region_variant, intron_variant	Intron 24 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5276 AN: 151328 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.00368

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0298

GnomAD2 exomes AF: 0.0351 AC: 8722 AN: 248442 AF XY: 0.0356

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.00496

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0380 AC: 55274 AN: 1454142 Hom.: 1135 Cov.: 33 AF XY: 0.0381 AC XY: 27568 AN XY: 723508

African (AFR) AF: 0.0378 AC: 1252 AN: 33140

American (AMR) AF: 0.0214 AC: 953 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 1713 AN: 26054

East Asian (EAS) AF: 0.00239 AC: 94 AN: 39390

South Asian (SAS) AF: 0.0371 AC: 3189 AN: 86008

European-Finnish (FIN) AF: 0.0255 AC: 1336 AN: 52360

Middle Eastern (MID) AF: 0.0625 AC: 279 AN: 4462

European-Non Finnish (NFE) AF: 0.0400 AC: 44284 AN: 1108172

Other (OTH) AF: 0.0363 AC: 2174 AN: 59966

GnomAD4 genome AF: 0.0349 AC: 5281 AN: 151444 Hom.: 98 Cov.: 32 AF XY: 0.0334 AC XY: 2472 AN XY: 73994

African (AFR) AF: 0.0347 AC: 1433 AN: 41298

American (AMR) AF: 0.0289 AC: 439 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 238 AN: 3452

East Asian (EAS) AF: 0.00330 AC: 17 AN: 5150

South Asian (SAS) AF: 0.0288 AC: 137 AN: 4750

European-Finnish (FIN) AF: 0.0191 AC: 201 AN: 10546

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0401 AC: 2718 AN: 67748

Other (OTH) AF: 0.0295 AC: 62 AN: 2102

Alfa AF: 0.0219 Hom.: 11

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0402

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 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. -

Jun 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4289-3_4289-2insC in intron 24 of MYLK: This variant is not expected to have c linical significance it has been identified in 5% (3279/66076) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs200371896, rs41431347). -

Aug 26, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYLK c.4289-3dupC alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.035 in 248442 control chromosomes in the gnomAD database, including 170 homozygotes. The observed variant frequency is approximately 1404 fold of 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.4289-3dupC in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

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

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 30, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41431347; hg19: chr3-123368043; COSMIC: COSV60608250; COSMIC: COSV60608250;