rs143896146

chr3-123739992-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.383C>T(p.Ala128Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,613,802 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A128T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (323 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.524

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=0.0015271008).
• BP6: Variant 3-123739992-G-A is Benign according to our data. Variant chr3-123739992-G-A is described in ClinVar as [Benign]. Clinvar id is 241759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123739992-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.383C>T	p.Ala128Val	missense_variant	6/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.383C>T	p.Ala128Val	missense_variant	6/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.00753 AC: 1146 AN: 152164 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0705

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: 0.000132

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0171 AC: 4302 AN: 251410 Hom.: 284 AF XY: 0.0132 AC XY: 1787 AN XY: 135870

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00361 AC: 5273 AN: 1461520 Hom.: 323 Cov.: 31 AF XY: 0.00304 AC XY: 2209 AN XY: 727042

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00752 AC: 1145 AN: 152282 Hom.: 50 Cov.: 33 AF XY: 0.00872 AC XY: 649 AN XY: 74450

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.000858 Hom.: 4

Bravo AF: 0.0134

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0128 AC: 1551

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala128Val in exon 6 of MYLK: This variant is not expected to have clinical signi ficance because it has been identified in 12.9% (17/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs143896146). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2019	Variant summary: MYLK c.383C>T (p.Ala128Val) 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 0.016 in 282808 control chromosomes, predominantly at a frequency of 0.12 within the Latino subpopulation in the gnomAD database, including 286 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database greatly exceeds 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 found primarily in populations of Latino origin. To our knowledge, no occurrence of c.383C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified 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	Oct 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	3.7
Dann	Benign	0.95
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0089	N
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.13	N;.;N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.69	T;.;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B;B
Vest4		0.081
MPC		0.19
ClinPred		0.0019	T
GERP RS		-2.1
Varity_R		0.020
gMVP		0.26

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: rs143896146; hg19: chr3-123458839;