rs761639849

Variant names:

• chr3-123722208-G-A
• rs761639849
• NM_053025.4:c.1724C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123722208-G-A
• chr3-123722208-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_053025.4(MYLK):​c.1724C>T​(p.Pro575Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,562,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P575S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.11
• Publications: 1 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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000631 (89/1409926) while in subpopulation SAS AF = 0.000251 (20/79826). AF 95% confidence interval is 0.000165. There are 0 homozygotes in GnomAdExome4. There are 50 alleles in the male GnomAdExome4 subpopulation. Median coverage is 42. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.1724C>T	p.Pro575Leu	missense	Exon 13 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1724C>T	p.Pro575Leu	missense	Exon 13 of 33	NP_444255.3
	MYLK	NM_053026.4		c.1517C>T	p.Pro506Leu	missense	Exon 12 of 33	NP_444254.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.1724C>T	p.Pro575Leu	missense	Exon 13 of 34	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.*1303C>T		non_coding_transcript_exon	Exon 12 of 33	ENSP00000417798.1
	MYLK	ENST00000464489.5	TSL:1	n.*1303C>T		3_prime_UTR	Exon 12 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000584 AC: 10 AN: 171140 AF XY: 0.0000880

Gnomad AFR exome AF: 0.000101

Gnomad AMR exome AF: 0.0000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.0000631 AC: 89 AN: 1409926 Hom.: 0 Cov.: 42 AF XY: 0.0000718 AC XY: 50 AN XY: 696438

African (AFR) AF: 0.0000310 AC: 1 AN: 32282

American (AMR) AF: 0.0000267 AC: 1 AN: 37424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.00 AC: 0 AN: 36666

South Asian (SAS) AF: 0.000251 AC: 20 AN: 79826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000599 AC: 65 AN: 1084854

Other (OTH) AF: 0.0000342 AC: 2 AN: 58432

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000423 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Aortic aneurysm, familial thoracic 7 (2)
-	2	-	Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (2)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.27	N
PhyloP100		5.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.36
Sift	Benign	0.29	T
Sift4G	Benign	0.11	T
Polyphen		0.93	P
Vest4		0.51
MutPred		0.54		Loss of disorder (P = 0.0276)
MVP		0.84
MPC		0.22
ClinPred		0.18	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.83
Mutation Taster		=62/38	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: rs761639849; hg19: chr3-123441055;