rs146990616

Variant names:

• chr3-123620185-GGCTGGAGAA-G
• rs146990616
• NM_053025.4:c.5368+13_5368+21delTTCTCCAGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_053025.4(MYLK):​c.5368+13_5368+21delTTCTCCAGC 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.5368+13_5368+21delTTCTCCAGC		intron_variant	Intron 32 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.5368+13_5368+21delTTCTCCAGC		intron_variant	Intron 32 of 33	5	NM_053025.4	ENSP00000353452.3

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

GnomAD2 exomes AF: 0.00511 AC: 1284 AN: 251332 AF XY: 0.00540

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 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 AC: 21 AN: 33246

Gnomad4 AMR exome AF: 0.00280 AC: 125 AN: 44712

Gnomad4 ASJ exome AF: 0.00617 AC: 161 AN: 26082

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39638

Gnomad4 SAS exome AF: 0.00252 AC: 217 AN: 86042

Gnomad4 FIN exome AF: 0.00537 AC: 287 AN: 53408

Gnomad4 NFE exome AF: 0.00771 AC: 8501 AN: 1102530

Gnomad4 Remaining exome AF: 0.00549 AC: 330 AN: 60060

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 AC: 0.00118181 AN: 0.00118181

Gnomad4 AMR AF: 0.00471 AC: 0.00471143 AN: 0.00471143

Gnomad4 ASJ AF: 0.00893 AC: 0.00892857 AN: 0.00892857

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00145 AC: 0.0014547 AN: 0.0014547

Gnomad4 FIN AF: 0.00530 AC: 0.00530403 AN: 0.00530403

Gnomad4 NFE AF: 0.00865 AC: 0.00864833 AN: 0.00864833

Gnomad4 OTH AF: 0.00523 AC: 0.00522814 AN: 0.00522814

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

Nov 27, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 22, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aortic aneurysm, familial thoracic 7 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism

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;