rs377231739

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_053025.4(MYLK):c.3843C>T(p.Ser1281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.496

Variant links:

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]

MYLK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 3-123664247-G-A is Benign according to our data. Variant chr3-123664247-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BP7

Synonymous conserved (PhyloP=-0.496 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.3843C>T	p.Ser1281=	synonymous_variant	23/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.3843C>T	p.Ser1281=	synonymous_variant	23/34	5	NM_053025.4	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250752

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000138

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 18, 2020	The MYLK c.3843C>T; p.Ser1281Ser variant (rs377231739), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 241760). This variant is found in the African population with an allele frequency of 0.03% (8/ 24948 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site/weakening the nearby canonical splice site. Due to limited information, the clinical significance of the p.Ser1281Ser variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	- -

MYLK-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2022

The MYLK c.3843C>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to create a novel cryptic donor splice site, based on available splicing prediction programs (Alamut Visual v2.11). However, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-123383094-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/241760/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Aortic aneurysm, familial thoracic 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

Cadd

Benign

8.0

Dann

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over