chr3-123739046-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_053025.4(MYLK):c.439C>T(p.Pro147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,613,666 control chromosomes in the GnomAD database, including 762,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 61300 hom., cov: 31)

Exomes 𝑓: 0.98 ( 700795 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.16

Publications

48 publications found

Variant links:

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
megacystis-microcolon-intestinal hypoperistalsis syndrome 1
Inheritance: AR Classification: STRONG Submitted by: G2P
familial thoracic aortic aneurysm and aortic dissection
Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
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

MYLK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.1008615E-7).

BP6

Variant 3-123739046-G-A is Benign according to our data. Variant chr3-123739046-G-A is described in ClinVar as Benign. ClinVar VariationId is 198606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.988 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYLK	NM_053025.4	MANE Select	c.439C>T	p.Pro147Ser	missense	Exon 7 of 34	NP_444253.3
MYLK	NM_053027.4		c.439C>T	p.Pro147Ser	missense	Exon 7 of 33	NP_444255.3
MYLK	NM_053026.4		c.439C>T	p.Pro147Ser	missense	Exon 7 of 33	NP_444254.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYLK	ENST00000360304.8	TSL:5 MANE Select	c.439C>T	p.Pro147Ser	missense	Exon 7 of 34	ENSP00000353452.3	Q15746-1
MYLK	ENST00000464489.5	TSL:1	n.*18C>T		non_coding_transcript_exon	Exon 6 of 33	ENSP00000417798.1	F8WBL7
MYLK	ENST00000464489.5	TSL:1	n.*18C>T		3_prime_UTR	Exon 6 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes

AF:

0.885

AC:

134504

AN:

151972

Hom.:

61294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.943

Gnomad ASJ

AF:

0.966

Gnomad EAS

AF:

0.938

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.962

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.995

Gnomad OTH

AF:

0.905

GnomAD2 exomes

AF:

0.948

AC:

237916

AN:

250870

AF XY:

0.954

show subpopulations

Gnomad AFR exome

AF:

0.632

Gnomad AMR exome

AF:

0.951

Gnomad ASJ exome

AF:

0.966

Gnomad EAS exome

AF:

0.937

Gnomad FIN exome

AF:

0.969

Gnomad NFE exome

AF:

0.994

Gnomad OTH exome

AF:

0.966

GnomAD4 exome

AF:

0.977

AC:

1428507

AN:

1461576

Hom.:

700795

Cov.:

AF XY:

0.977

AC XY:

710333

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.624

AC:

20876

AN:

33474

American (AMR)

AF:

0.949

AC:

42414

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

25145

AN:

26120

East Asian (EAS)

AF:

0.938

AC:

37252

AN:

39696

South Asian (SAS)

AF:

0.928

AC:

79915

AN:

86120

European-Finnish (FIN)

AF:

0.973

AC:

51985

AN:

53404

Middle Eastern (MID)

AF:

0.960

AC:

5537

AN:

5768

European-Non Finnish (NFE)

AF:

0.996

AC:

1107640

AN:

1111926

Other (OTH)

AF:

0.956

AC:

57743

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1759

3517

5276

7034

8793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21624

43248

64872

86496

108120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.885

AC:

134547

AN:

152090

Hom.:

61300

Cov.:

AF XY:

0.886

AC XY:

65882

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.641

AC:

26548

AN:

41418

American (AMR)

AF:

0.943

AC:

14435

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.966

AC:

3354

AN:

3472

East Asian (EAS)

AF:

0.938

AC:

4820

AN:

5136

South Asian (SAS)

AF:

0.922

AC:

4437

AN:

4814

European-Finnish (FIN)

AF:

0.962

AC:

10205

AN:

10606

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.995

AC:

67651

AN:

68022

Other (OTH)

AF:

0.903

AC:

1911

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

617

1234

1852

2469

3086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.963

Hom.:

252736

Bravo

AF:

0.872

TwinsUK

AF:

0.996

AC:

3694

ALSPAC

AF:

0.997

AC:

3844

ESP6500AA

AF:

0.637

AC:

2808

ESP6500EA

AF:

0.993

AC:

8539

ExAC

AF:

0.944

AC:

114556

Asia WGS

AF:

0.890

AC:

3094

AN:

3478

EpiCase

AF:

0.993

EpiControl

AF:

0.993

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Aortic aneurysm, familial thoracic 7 (4)

not provided (3)

Familial thoracic aortic aneurysm and aortic dissection (1)

Megacystis, microcolon, hypoperistalsis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.29

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.85

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.75

MetaRNN

Benign

6.1e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

PhyloP100

3.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

REVEL

Benign

0.088

Sift

Benign

0.29

Sift4G

Uncertain

0.0090

Polyphen

0.095

Vest4

0.13

MPC

0.16

ClinPred

0.0077

GERP RS

1.3

Varity_R

0.037

gMVP

0.49

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over