rs146990616

Positions:

• chr3-123620185-GGCTGGAGAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23

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

ACMG classification

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	c.5368+13_5368+21del		intron_variant		ENST00000360304.8
MYLK-AS1	NR_038266.2	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	c.5368+13_5368+21del		intron_variant		5	NM_053025.4	P4
MYLK-AS1	ENST00000485162.5	n.261-9308_261-9300del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 817 AN: 151960 Hom.: 2 Cov.: 32

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.: 8 AF XY: 0.00540 AC XY: 733 AN XY: 135846

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.: 40 AF XY: 0.00658 AC XY: 4759 AN XY: 722778

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.: 2 Cov.: 32 AF XY: 0.00509 AC XY: 378 AN XY: 74316

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.: 0

Bravo AF: 0.00469

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146990616; hg19: chr3-123339032;