3-123744861-C-T

Variant names:

• chr3-123744861-C-T
• rs11718105
• NM_053025.4:c.374-4860G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_053025.4(MYLK):​c.374-4860G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,044 control chromosomes in the GnomAD database, including 6,625 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6625 hom., cov: 32)
• Consequence: MYLK NM_053025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.374-4860G>A		intron_variant	Intron 5 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.374-4860G>A		intron_variant	Intron 5 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39692 AN: 151926 Hom.: 6625 Cov.: 32

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.261 AC: 39685 AN: 152044 Hom.: 6625 Cov.: 32 AF XY: 0.257 AC XY: 19093 AN XY: 74326

African (AFR) AF: 0.0866 AC: 3594 AN: 41492

American (AMR) AF: 0.234 AC: 3569 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3468

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5182

South Asian (SAS) AF: 0.155 AC: 747 AN: 4822

European-Finnish (FIN) AF: 0.357 AC: 3759 AN: 10536

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25615 AN: 67962

Other (OTH) AF: 0.294 AC: 621 AN: 2112

Alfa AF: 0.346 Hom.: 12006

Bravo AF: 0.246

Asia WGS AF: 0.0830 AC: 291 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.48
PhyloP100		0.015
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11718105; hg19: chr3-123463708; COSMIC: COSV60607220;