rs3732485

chr3-123700935-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):c.2533C>T(p.Arg845Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,056 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. R845P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (62 hom., cov: 30)
  • Exomes 𝑓: 0.012 (586 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0490

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]

LOC105369194 (HGNC:):

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=0.0014624298).
• BP6: Variant 3-123700935-G-A is Benign according to our data. Variant chr3-123700935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700935-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.2533C>T	p.Arg845Cys	missense_variant	18/34	ENST00000360304.8
LOC105369194	XR_924417.4	n.108-2931G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.2533C>T	p.Arg845Cys	missense_variant	18/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2477 AN: 152010 Hom.: 62 Cov.: 30

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0856

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0270 AC: 6650 AN: 246212 Hom.: 240 AF XY: 0.0293 AC XY: 3925 AN XY: 134066

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.0505

Gnomad SAS exome AF: 0.0888

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0117 AC: 17118 AN: 1458928 Hom.: 586 Cov.: 39 AF XY: 0.0140 AC XY: 10192 AN XY: 725962

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.0871

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0163 AC: 2484 AN: 152128 Hom.: 62 Cov.: 30 AF XY: 0.0200 AC XY: 1490 AN XY: 74344

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0481

Gnomad4 SAS AF: 0.0857

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00619 Hom.: 3

Bravo AF: 0.0117

ESP6500AA AF: 0.0139 AC: 61

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.0265 AC: 3213

Asia WGS AF: 0.0750 AC: 259 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

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	Arg845Cys in exon 18 of MYLK: This variant is not expected to have clinical sign ificance because it has been identified in 1.4% (61/4402) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs3732485). -
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	Feb 17, 2020	Variant summary: MYLK c.2533C>T (p.Arg845Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 246212 control chromosomes in the gnomAD database, including 240 homozygotes. The observed variant frequency is approximately 1080-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 benign. To our knowledge, no occurrence of c.2533C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2016	- -
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, 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 12, 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:2

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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 01, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 01, 2023

- -

Aortic aneurysm, familial thoracic 6 Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Benign	0.96
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.053	N
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.58	N;.;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.25	T;.;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.021	B;B;B;B;B;B
Vest4		0.083
MPC		0.22
ClinPred		0.0016	T
GERP RS		1.3
Varity_R		0.048
gMVP		0.21

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: rs3732485; hg19: chr3-123419782; COSMIC: COSV60619931; COSMIC: COSV60619931;