rs755451013

Variant names:

• chr3-123734196-G-A
• rs755451013
• NM_053025.4:c.800C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123734196-G-A
• chr3-123734196-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053025.4(MYLK):​c.800C>T​(p.Thr267Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T267N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05672252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.800C>T	p.Thr267Ile	missense_variant	Exon 10 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.800C>T	p.Thr267Ile	missense_variant	Exon 10 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000520 AC: 1 AN: 192284 AF XY: 0.00000974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391528 Hom.: 0 Cov.: 53 AF XY: 0.00000146 AC XY: 1 AN XY: 687010

African (AFR) AF: 0.00 AC: 0 AN: 31442

American (AMR) AF: 0.00 AC: 0 AN: 36592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22310

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 75438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086086

Other (OTH) AF: 0.00 AC: 0 AN: 57688

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Benign	0.83
DEOGEN2	Benign	0.20	.;.;.;T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.82	.;T;T;T;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N;N;N
PhyloP100		0.096
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.66	N;.;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.48	T;.;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T
Polyphen		0.026	B;B;B;B;B;B
Vest4		0.061
MutPred		0.29		Loss of ubiquitination at K265 (P = 0.0432);Loss of ubiquitination at K265 (P = 0.0432);Loss of ubiquitination at K265 (P = 0.0432);Loss of ubiquitination at K265 (P = 0.0432);Loss of ubiquitination at K265 (P = 0.0432);Loss of ubiquitination at K265 (P = 0.0432);
MVP		0.60
MPC		0.24
ClinPred		0.035	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.064
Mutation Taster		=98/2	polymorphism

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: rs755451013; hg19: chr3-123453043;