rs113124819

chr3-123666344-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP2 PP3_Moderate BP6

The NM_053025.4(MYLK):c.3706A>G(p.Met1236Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: MYLK NM_053025.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.349

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 Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-123666344-T-C is Benign according to our data. Variant chr3-123666344-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.3706A>G	p.Met1236Val	missense_variant, splice_region_variant	22/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.3706A>G	p.Met1236Val	missense_variant, splice_region_variant	22/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000270 AC: 68 AN: 251394 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135860

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000202

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461890 Hom.: 3 Cov.: 32 AF XY: 0.000153 AC XY: 111 AN XY: 727244

Gnomad4 AFR exome AF: 0.00463

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74462

Gnomad4 AFR AF: 0.00306

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 14, 2022	This missense variant represents an amino acid change of methionine with valine in codon 1236 of the MYLK gene; this codon is also within the splice region at the start of exon 22. This variant occurs in gnomAD with a total MAF of 0.0260% and highest MAF of 0.3790% in the African population, which is inconsistent with disease frequency. This position is not conserved. In silico functional models PolyPhen and SIFT predict this variant to be benign/tolerated; similarly, in silico splicing algorithms do not predict an impact to the splice site (MaxEntScan: 0.587). However, experimental functional or protein studies have not been performed to confirm these predictions. This variant is not present in the literature in association with disease. Considering this variant occurs relatively frequently and is not predicted to impact the protein or splicing, it is considered Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2020	This alteration is classified as likely 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2021	- -

Aortic aneurysm, familial thoracic 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	25
Dann	Benign	0.91
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0066	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;.;N;N;.;N;.
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.79	N;.;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.60	T;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;.
Polyphen		0.0010	B;B;B;B;B;B;.
Vest4		0.18
MVP		0.67
MPC		0.17
ClinPred		0.0079	T
GERP RS		3.1
Varity_R		0.072
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113124819; hg19: chr3-123385191; COSMIC: COSV60611926; COSMIC: COSV60611926;