rs35156360

Positions:

• chr3-123733085-G-A
• chr3-123733085-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P443T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (255 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.88

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• 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	UniProt
MYLK	NM_053025.4	c.1327C>T	p.Pro443Ser	missense_variant	11/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.1327C>T	p.Pro443Ser	missense_variant	11/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152138 Hom.: 16 Cov.: 32

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.: 32 AF XY: 0.0147 AC XY: 1989 AN XY: 134866

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.: 35 AF XY: 0.0175 AC XY: 12720 AN XY: 727074

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.: 15 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74426

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.: 48

Bravo AF: 0.0121

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00477 AC: 21

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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, 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	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Aortic aneurysm, familial thoracic 7 Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYLK: BP4, BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0074	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs35156360; hg19: chr3-123451932; COSMIC: COSV60610441; COSMIC: COSV60610441;