rs149530842

Positions:

• chr3-123664192-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_053025.4(MYLK):​c.3898G>A​(p.Ala1300Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1300V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 0.916

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYLK
• BP4: Computational evidence support a benign effect (MetaRNN=0.012942165).
• BP6: Variant 3-123664192-C-T is Benign according to our data. Variant chr3-123664192-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 342880.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=6}. Variant chr3-123664192-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.3898G>A	p.Ala1300Thr	missense_variant	23/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.3898G>A	p.Ala1300Thr	missense_variant	23/34	5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251312 Hom.: 0 AF XY: 0.000493 AC XY: 67 AN XY: 135832

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000261 AC: 382 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 196 AN XY: 727234

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74452

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000680

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 7 Uncertain:2 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	MYLK NM_053026 exon22 p.Ala1231Thr (c.3691G>A): This variant has not been reported in the literature but is present in 0.1% (58/34412) of Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs149530842). This variant is present in ClinVar (Variation ID:342880). This variant threonine (Thr) is present in >10 species including mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MYLK: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	- -

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	Apr 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2019	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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

MYLK NM_053026 exon22 p.Ala1231Thr (c.3691G>A): This variant has not been reported in the literature but is present in 0.1% (58/34412) of Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs149530842). This variant is present in ClinVar (Variation ID:342880). This variant threonine (Thr) is present in >10 species including mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

MYLK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.39	N;.;N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N;.;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.43	T;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;.
Polyphen		0.0030	B;B;B;B;B;B;.
Vest4		0.31
MVP		0.69
MPC		0.35
ClinPred		0.011	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.28

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: rs149530842; hg19: chr3-123383039; COSMIC: COSV60624724; COSMIC: COSV60624724;