Genetic Variant NM_053025.4:c.3558C>T (chr3-123692742-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_053025.4(MYLK):c.3558C>T(p.Thr1186Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,124 control chromosomes in the GnomAD database, including 405,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1186T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.53 ( 26879 hom., cov: 31)

Exomes 𝑓: 0.70 ( 378592 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.44

Publications

17 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 links:

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

MYLK-AS1 links:

LOC105369194 (HGNC:):

LOC105369194 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 3-123692742-G-A is Benign according to our data. Variant chr3-123692742-G-A is described in ClinVar as Benign. ClinVar VariationId is 226764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 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.3558C>T	p.Thr1186Thr	synonymous	Exon 19 of 34	NP_444253.3
MYLK	NM_053027.4		c.3558C>T	p.Thr1186Thr	synonymous	Exon 19 of 33	NP_444255.3
MYLK	NM_053026.4		c.3351C>T	p.Thr1117Thr	synonymous	Exon 18 of 33	NP_444254.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYLK	ENST00000360304.8	TSL:5 MANE Select	c.3558C>T	p.Thr1186Thr	synonymous	Exon 19 of 34	ENSP00000353452.3
MYLK	ENST00000504946.6	TSL:1	c.1167C>T	p.Thr389Thr	synonymous	Exon 3 of 4	ENSP00000510315.1
MYLK	ENST00000464489.5	TSL:1	n.*3137C>T		non_coding_transcript_exon	Exon 18 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes

AF:

0.531

AC:

80623

AN:

151868

Hom.:

26882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.808

Gnomad AMR

AF:

0.528

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.0482

Gnomad SAS

AF:

0.450

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.760

Gnomad OTH

AF:

0.570

GnomAD2 exomes

AF:

0.579

AC:

145353

AN:

251122

AF XY:

0.594

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.449

Gnomad ASJ exome

AF:

0.767

Gnomad EAS exome

AF:

0.0439

Gnomad FIN exome

AF:

0.636

Gnomad NFE exome

AF:

0.761

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.699

AC:

1021051

AN:

1460138

Hom.:

378592

Cov.:

AF XY:

0.696

AC XY:

505398

AN XY:

726514

show subpopulations

African (AFR)

AF:

0.148

AC:

4948

AN:

33462

American (AMR)

AF:

0.460

AC:

20579

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

20078

AN:

26118

East Asian (EAS)

AF:

0.0336

AC:

1335

AN:

39690

South Asian (SAS)

AF:

0.487

AC:

41950

AN:

86212

European-Finnish (FIN)

AF:

0.642

AC:

34144

AN:

53190

Middle Eastern (MID)

AF:

0.705

AC:

4043

AN:

5736

European-Non Finnish (NFE)

AF:

0.770

AC:

854773

AN:

1110692

Other (OTH)

AF:

0.650

AC:

39201

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

14422

28844

43266

57688

72110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19912

39824

59736

79648

99560

<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:

0.530

AC:

80610

AN:

151986

Hom.:

26879

Cov.:

AF XY:

0.521

AC XY:

38722

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.169

AC:

7013

AN:

41470

American (AMR)

AF:

0.528

AC:

8059

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2656

AN:

3472

East Asian (EAS)

AF:

0.0479

AC:

248

AN:

5174

South Asian (SAS)

AF:

0.451

AC:

2160

AN:

4794

European-Finnish (FIN)

AF:

0.634

AC:

6685

AN:

10552

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.760

AC:

51654

AN:

67930

Other (OTH)

AF:

0.563

AC:

1190

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1389

2779

4168

5558

6947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.681

Hom.:

106957

Bravo

AF:

0.508

Asia WGS

AF:

0.254

AC:

890

AN:

3478

EpiCase

AF:

0.769

EpiControl

AF:

0.768

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Aortic aneurysm, familial thoracic 7 (4)

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

Megacystis, microcolon, hypoperistalsis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.9

(source)

DANN

Benign

0.88

PhyloP100

-1.4

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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