rs146990616

Positions:

chr3-123620185-GGCTGGAGAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_053025.4(MYLK):c.5368+13_5368+21del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,603,516 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 40 hom. )

Consequence

MYLK
NM_053025.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.23

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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

MYLK-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 3-123620185-GGCTGGAGAA-G is Benign according to our data. Variant chr3-123620185-GGCTGGAGAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 420653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123620185-GGCTGGAGAA-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00537 (817/152046) while in subpopulation NFE AF= 0.00865 (588/67990). AF 95% confidence interval is 0.00807. There are 2 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.5368+13_5368+21del		intron_variant		ENST00000360304.8
MYLK-AS1	NR_038266.2 linkuse as main transcript	n.290-9308_290-9300del		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.5368+13_5368+21del		intron_variant		5	NM_053025.4	P4	Q15746-1
MYLK-AS1	ENST00000485162.5 linkuse as main transcript	n.261-9308_261-9300del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

817

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00530

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00865

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00511

AC:

1284

AN:

251332

Hom.:

AF XY:

0.00540

AC XY:

733

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.00794

Gnomad OTH exome

AF:

0.00537

GnomAD4 exome

AF:

0.00665

AC:

9649

AN:

1451470

Hom.:

AF XY:

0.00658

AC XY:

4759

AN XY:

722778

show subpopulations

Gnomad4 AFR exome

AF:

0.000632

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00617

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00252

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.00771

Gnomad4 OTH exome

AF:

0.00549

GnomAD4 genome

AF:

0.00537

AC:

817

AN:

152046

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

378

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00530

Gnomad4 NFE

AF:

0.00865

Gnomad4 OTH

AF:

0.00523

Alfa

AF:

0.00709

Hom.:

Bravo

AF:

0.00469

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2021	Variant summary: MYLK c.5368+13_5368+21delTTCTCCAGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.0051 in 251332 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 102-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Thoracic Aortic Aneurysms And Dissections phenotype (5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5368+13_5368+21delTTCTCCAGC in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite 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	Nov 27, 2017	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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 27, 2023

- -

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

Splicing

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