rs820463

Positions:

• chr3-123638190-A-G
• chr3-123638190-A-T

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.4842T>C​(p.Asn1614=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,612,880 control chromosomes in the GnomAD database, including 30,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (6022 hom., cov: 32)
  • Exomes 𝑓: 0.13 (24188 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0920

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]

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-123638190-A-G is Benign according to our data. Variant chr3-123638190-A-G is described in ClinVar as [Benign]. Clinvar id is 226771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123638190-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.4842T>C	p.Asn1614=	synonymous_variant	29/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.4842T>C	p.Asn1614=	synonymous_variant	29/34	5	NM_053025.4	P4
MYLK-AS1	ENST00000485162.5	n.523-6314A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34032 AN: 151920 Hom.: 5995 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.220 AC: 55157 AN: 250898 Hom.: 9919 AF XY: 0.208 AC XY: 28188 AN XY: 135620

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.608

Gnomad SAS exome AF: 0.285

Gnomad FIN exome AF: 0.0804

Gnomad NFE exome AF: 0.0873

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.130 AC: 189516 AN: 1460842 Hom.: 24188 Cov.: 33 AF XY: 0.132 AC XY: 96137 AN XY: 726720

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.644

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.0787

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.224 AC: 34128 AN: 152038 Hom.: 6022 Cov.: 32 AF XY: 0.228 AC XY: 16931 AN XY: 74316

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.621

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.0691

Gnomad4 NFE AF: 0.0852

Gnomad4 OTH AF: 0.202

Alfa AF: 0.121 Hom.: 2226

Bravo AF: 0.252

Asia WGS AF: 0.459 AC: 1593 AN: 3478

EpiCase AF: 0.0895

EpiControl AF: 0.0911

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Asn1614Asn in exon 29 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 40.8% (1798/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs820463). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

Aortic aneurysm, familial thoracic 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.053
DANN	Benign	0.55

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: rs820463; hg19: chr3-123357037; COSMIC: COSV60607062; COSMIC: COSV60607062;