rs4677905

Variant names:

• chr3-123805987-T-A
• rs4677905
• NM_053025.4:c.-3-12143A>T

Variant summary

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

The NM_053025.4(MYLK):​c.-3-12143A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,242 control chromosomes in the GnomAD database, including 2,981 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 0.18 (2981 hom., cov: 33)
• Consequence: MYLK NM_053025.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 2 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.-3-12143A>T		intron	N/A	NP_444253.3
	MYLK	NM_053027.4		c.-3-12143A>T		intron	N/A	NP_444255.3
	MYLK	NM_053026.4		c.-3-12143A>T		intron	N/A	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.-3-12143A>T		intron	N/A	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.-3-12143A>T		intron	N/A	ENSP00000417798.1
	MYLK	ENST00000687848.1		c.28-12143A>T		intron	N/A	ENSP00000508761.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27681 AN: 152124 Hom.: 2980 Cov.: 33

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.182 AC: 27695 AN: 152242 Hom.: 2981 Cov.: 33 AF XY: 0.181 AC XY: 13490 AN XY: 74438

African (AFR) AF: 0.0892 AC: 3706 AN: 41556

American (AMR) AF: 0.137 AC: 2099 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 703 AN: 3472

East Asian (EAS) AF: 0.0287 AC: 149 AN: 5186

South Asian (SAS) AF: 0.166 AC: 803 AN: 4824

European-Finnish (FIN) AF: 0.264 AC: 2797 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16682 AN: 68004

Other (OTH) AF: 0.191 AC: 402 AN: 2110

Alfa AF: 0.211 Hom.: 475

Bravo AF: 0.169

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.7
DANN	Benign	0.88
PhyloP100		0.033
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: rs4677905; hg19: chr3-123524834;