rs35156360

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_053025.4(MYLK):c.1327C>T(p.Pro443Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0171 in 1,613,872 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 32)

Exomes 𝑓: 0.018 ( 255 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.88

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 Benign. Variant got -19 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.007373214).

BP6

Variant 3-123733085-G-A is Benign according to our data. Variant chr3-123733085-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123733085-G-A is described in Lovd as [Benign]. Variant chr3-123733085-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1863/152256) while in subpopulation NFE AF= 0.0188 (1281/68014). AF 95% confidence interval is 0.018. There are 15 homozygotes in gnomad4. There are 856 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.1327C>T	p.Pro443Ser	missense_variant	11/34	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.1327C>T	p.Pro443Ser	missense_variant	11/34	5	NM_053025.4	ENSP00000353452	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1865

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00838

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0141

AC:

3514

AN:

249246

Hom.:

AF XY:

0.0147

AC XY:

1989

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.00774

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0161

Gnomad FIN exome

AF:

0.00793

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0176

AC:

25769

AN:

1461616

Hom.:

255

Cov.:

AF XY:

0.0175

AC XY:

12720

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.00790

Gnomad4 ASJ exome

AF:

0.0317

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0156

Gnomad4 FIN exome

AF:

0.00800

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0122

AC:

1863

AN:

152256

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

856

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00378

Gnomad4 AMR

AF:

0.00836

Gnomad4 ASJ

AF:

0.0320

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0158

Gnomad4 FIN

AF:

0.00622

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0170

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0205

AC:

176

ExAC

AF:

0.0144

AC:

1748

EpiCase

AF:

0.0206

EpiControl

AF:

0.0196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Pro443Ser in exon 11 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 2.0% (176/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35156360). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2019	Variant summary: MYLK c.1327C>T (p.Pro443Ser) results in a non-conservative amino acid change located in one of the immunoglobulin subtype 2 domains (IPR003598) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.014 in 280644 control chromosomes (predominantly reported within the Ashkenazi Jewish and Non-Finnish European subpopulations) in the gnomAD database, including 35 homozygotes. The observed variant frequency within the gnomAD database is approximately 500 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 a benign polymorphism. Though the variant, c.1327C>T, has been reported to be found in a cohort of patients with familial abdominal aortic aneurysm, however, the variant was noted to be a part of complex genotypes, and it did not segregate with the disease in at least one family (van de Luijtgaarden_2015). To our knowledge no experimental evidence demonstrating its impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cites the variant five times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYLK: BP4, BS1, BS2 -

Aortic aneurysm, familial thoracic 7

Benign:2

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

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 30, 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. -

Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 02, 2022

MYLK NM_053025.3 exon 11 p.Pro443Ser (c.1327C>T): This variant has been reported in the literature in one individual with an abdominal aortic aneurysm (van de Luijtgaarden 2015 PMID:26017485). However, this variant is also present in 1.8% (1212/64560) of European alleles in the Genome Aggregation Database, including 11 homozygotes (https://gnomad.broadinstitute.org/variant/3-123733085-G-A?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:226754). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

.;.;D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

.;D;D;.

MetaRNN

Benign

0.0074

T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.3

M;M;M;M

MutationTaster

Benign

0.95

D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.58

MPC

0.18

ClinPred

0.034

GERP RS

5.4

Varity_R

0.79

gMVP

0.65

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