rs763880352

Positions:

chr3-123647278-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_053025.4(MYLK):c.4565T>C(p.Val1522Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 9.29

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.4565T>C	p.Val1522Ala	missense_variant	27/34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.4565T>C	p.Val1522Ala	missense_variant	27/34	5	NM_053025.4	ENSP00000353452	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251462

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 23, 2018	The MYLK c.4565T>C; p.Val1522Ala variant (rs763880352), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 12 out of 277,196 chromosomes) and is classified as a variant of uncertain significance in ClinVar (ID: 409680). The valine at position 1522 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Val1522Ala variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Val1522Ala variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2023	Reported in a 62-year-old Dutch male with aneurysms of the aortic root and ascending aorta, right bundle branch block, and skeletal features suggestive of a connective tissue disorder; this variant was also present in his similarly affected brother (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907982, 26582918) -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 22, 2024	The p.V1522A variant (also known as c.4565T>C), located in coding exon 24 of the MYLK gene, results from a T to C substitution at nucleotide position 4565. The valine at codon 1522 is replaced by alanine, an amino acid with similar properties. This alteration was detected in a cohort of individuals with familial or early onset aortic aneurysms/dissections or signs of generalized connective tissue disorders. Authors noted that it segregated with disease in at least one family member; however, no specific details were provided (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aortic aneurysm, familial thoracic 7

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1522 of the MYLK protein (p.Val1522Ala). This variant is present in population databases (rs763880352, gnomAD 0.009%). This missense change has been observed in individuals with aortic aneurysm (PMID: 29907982; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 409680). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYLK protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

MYLK-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2023

The MYLK c.4565T>C variant is predicted to result in the amino acid substitution p.Val1522Ala. This variant was reported in an individual with a suspected heritable thoracic aortic disorder (Table S1, Patient ID 122, Overwater et al. 2018. PubMed ID: 29907982). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-123366125-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;.;T;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

.;T;D;T;.;.

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.8

L;.;L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

D;.;D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;.;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

0.97

D;D;D;D;D;D

Vest4

0.82

MutPred

0.76

Loss of stability (P = 0.0623);.;Loss of stability (P = 0.0623);Loss of stability (P = 0.0623);.;Loss of stability (P = 0.0623);

MVP

0.80

MPC

1.0

ClinPred

0.46

GERP RS

5.4

Varity_R

0.37

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over