chr3-123682213-C-T

Position:

chr3-123682213-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000504946.6(MYLK):c.1272G>A(p.Ser424Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,590,224 control chromosomes in the GnomAD database, including 1,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 109 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1518 hom. )

Consequence

MYLK
ENST00000504946.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.767

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:

MYLK (HGNC:):

MYLK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 3-123682213-C-T is Benign according to our data. Variant chr3-123682213-C-T is described in ClinVar as [Benign]. Clinvar id is 226765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123682213-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0323 (4914/152190) while in subpopulation NFE AF= 0.0465 (3163/67996). AF 95% confidence interval is 0.0452. There are 109 homozygotes in gnomad4. There are 2466 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 109 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.3652+11G>A		intron_variant		ENST00000360304.8	NP_444253.3	Q15746-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8 linkuse as main transcript	c.3652+11G>A		intron_variant		5	NM_053025.4	ENSP00000353452.3		Q15746-1

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4916

AN:

152072

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00835

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0211

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0266

Gnomad FIN

AF:

0.0700

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0248

GnomAD3 exomes

AF:

0.0339

AC:

7349

AN:

216504

Hom.:

169

AF XY:

0.0349

AC XY:

4034

AN XY:

115530

show subpopulations

Gnomad AFR exome

AF:

0.00725

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000306

Gnomad SAS exome

AF:

0.0308

Gnomad FIN exome

AF:

0.0650

Gnomad NFE exome

AF:

0.0447

Gnomad OTH exome

AF:

0.0373

GnomAD4 exome

AF:

0.0429

AC:

61665

AN:

1438034

Hom.:

1518

Cov.:

AF XY:

0.0429

AC XY:

30573

AN XY:

712922

show subpopulations

Gnomad4 AFR exome

AF:

0.00595

Gnomad4 AMR exome

AF:

0.0158

Gnomad4 ASJ exome

AF:

0.0252

Gnomad4 EAS exome

AF:

0.000179

Gnomad4 SAS exome

AF:

0.0297

Gnomad4 FIN exome

AF:

0.0620

Gnomad4 NFE exome

AF:

0.0474

Gnomad4 OTH exome

AF:

0.0377

GnomAD4 genome

AF:

0.0323

AC:

4914

AN:

152190

Hom.:

109

Cov.:

AF XY:

0.0332

AC XY:

2466

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00833

Gnomad4 AMR

AF:

0.0211

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0268

Gnomad4 FIN

AF:

0.0700

Gnomad4 NFE

AF:

0.0465

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0381

Hom.:

Bravo

AF:

0.0275

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	3652+11G>A in intron 20 of MYLK: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 4.5% (386/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs41271437). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: MYLK c.3652+11G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.034 in 247866 control chromosomes in the gnomAD database, including 191 homozygotes. The observed variant frequency is approximately 1366-folds over the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aortic aneurysm, familial thoracic 7

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.8

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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