rs17298941

chr3-123657220-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):c.4194C>T(p.His1398=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,614,104 control chromosomes in the GnomAD database, including 1,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (67 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1066 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.13

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-123657220-G-A is Benign according to our data. Variant chr3-123657220-G-A is described in ClinVar as [Benign]. Clinvar id is 226767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123657220-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.4194C>T	p.His1398=	synonymous_variant	24/34	ENST00000360304.8
LOC124909421	XR_007096038.1	n.1066-1649G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.4194C>T	p.His1398=	synonymous_variant	24/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3826 AN: 152098 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0301 AC: 7575 AN: 251456 Hom.: 148 AF XY: 0.0314 AC XY: 4271 AN XY: 135912

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0432

GnomAD4 exome AF: 0.0353 AC: 51574 AN: 1461888 Hom.: 1066 Cov.: 32 AF XY: 0.0355 AC XY: 25813 AN XY: 727248

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0269

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0309

GnomAD4 genome AF: 0.0251 AC: 3825 AN: 152216 Hom.: 67 Cov.: 32 AF XY: 0.0240 AC XY: 1789 AN XY: 74414

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0338 Hom.: 75

Bravo AF: 0.0254

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0364

EpiControl AF: 0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	His1398His in exon 24 of MYLK: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 3.9% (339/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17298941). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 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. -

Aortic aneurysm, familial thoracic 7 Benign:2

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

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	6.2
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17298941; hg19: chr3-123376067;