3-123700066-G-A

Position:

chr3-123700066-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_053025.4(MYLK):c.3402C>T(p.Asn1134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,613,902 control chromosomes in the GnomAD database, including 789,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68730 hom., cov: 29)

Exomes 𝑓: 0.99 ( 721059 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.47

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:

LOC105369194 (HGNC:):

LOC105369194 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 3-123700066-G-A is Benign according to our data. Variant chr3-123700066-G-A is described in ClinVar as [Benign]. Clinvar id is 194903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700066-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.3402C>T	p.Asn1134=	synonymous_variant	18/34	ENST00000360304.8
LOC105369194	XR_924417.4 linkuse as main transcript	n.108-3800G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.3402C>T	p.Asn1134=	synonymous_variant	18/34	5	NM_053025.4	P4	Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.948

AC:

143999

AN:

151896

Hom.:

68696

Cov.:

show subpopulations

Gnomad AFR

AF:

0.826

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.974

Gnomad ASJ

AF:

0.988

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.953

GnomAD3 exomes

AF:

0.985

AC:

247623

AN:

251454

Hom.:

122159

AF XY:

0.988

AC XY:

134289

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.827

Gnomad AMR exome

AF:

0.987

Gnomad ASJ exome

AF:

0.985

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.998

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.987

GnomAD4 exome

AF:

0.993

AC:

1451405

AN:

1461888

Hom.:

721059

Cov.:

AF XY:

0.993

AC XY:

722475

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.827

Gnomad4 AMR exome

AF:

0.984

Gnomad4 ASJ exome

AF:

0.984

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.998

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.998

Gnomad4 OTH exome

AF:

0.984

GnomAD4 genome

AF:

0.948

AC:

144087

AN:

152014

Hom.:

68730

Cov.:

AF XY:

0.950

AC XY:

70597

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.826

Gnomad4 AMR

AF:

0.974

Gnomad4 ASJ

AF:

0.988

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.998

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.998

Gnomad4 OTH

AF:

0.953

Alfa

AF:

0.976

Hom.:

37391

Bravo

AF:

0.940

Asia WGS

AF:

0.989

AC:

3439

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Asn1134Asn in exon 18 of MYLK: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 16.5% (728/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs865358). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aortic aneurysm, familial thoracic 7

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, 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 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:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 11, 2016

Variant summary: MYLK c.3402C>T variant affects a conserved nucleotide, resulting in no amino acid change. Mutation Taster predicts the variant is a polymorphism, and 5/5 Alamut algorithms predict no significant effect on splicing. However, these predictions have not been verified with functional studies. This variant is found in 119276/121410 control chromosomes (58732 homozygotes) at a frequency of 0.9824232, which is about 78593 times of maximal expected frequency of a pathogenic allele (0.0000125), suggesting this variant is the ancestral allele and is benign. Taken together, this variant was classified as benign. -

Megacystis, microcolon, hypoperistalsis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.2

DANN

Benign

0.67

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