rs3732487

Variant names:

• chr3-123700726-G-T
• rs3732487
• NM_053025.4:c.2742C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-123700726-G-T
• chr3-123700726-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.2742C>A​(p.Asp914Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 1,613,966 control chromosomes in the GnomAD database, including 10,207 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D914G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.078 (1373 hom., cov: 31)
  • Exomes 𝑓: 0.049 (8834 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.167
• Publications: 18 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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

LOC105369194 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.6468763E-4).
• BP6: Variant 3-123700726-G-T is Benign according to our data. Variant chr3-123700726-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 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.2742C>A	p.Asp914Glu	missense	Exon 18 of 34	NP_444253.3
	MYLK	NM_053027.4		c.2742C>A	p.Asp914Glu	missense	Exon 18 of 33	NP_444255.3
	MYLK	NM_053026.4		c.2535C>A	p.Asp845Glu	missense	Exon 17 of 33	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.2742C>A	p.Asp914Glu	missense	Exon 18 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000504946.6	TSL:1	c.351C>A	p.Asp117Glu	missense	Exon 2 of 4	ENSP00000510315.1	A0A8I5KYZ0
	MYLK	ENST00000464489.5	TSL:1	n.*2321C>A		non_coding_transcript_exon	Exon 17 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11825 AN: 151972 Hom.: 1362 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.102 AC: 25615 AN: 251448 AF XY: 0.105

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.0498

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.561

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0494 AC: 72157 AN: 1461876 Hom.: 8834 Cov.: 40 AF XY: 0.0546 AC XY: 39683 AN XY: 727240

African (AFR) AF: 0.125 AC: 4179 AN: 33480

American (AMR) AF: 0.0477 AC: 2134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 618 AN: 26136

East Asian (EAS) AF: 0.482 AC: 19151 AN: 39698

South Asian (SAS) AF: 0.242 AC: 20868 AN: 86258

European-Finnish (FIN) AF: 0.0718 AC: 3837 AN: 53408

Middle Eastern (MID) AF: 0.0354 AC: 204 AN: 5768

European-Non Finnish (NFE) AF: 0.0148 AC: 16480 AN: 1112010

Other (OTH) AF: 0.0776 AC: 4686 AN: 60394

GnomAD4 genome AF: 0.0780 AC: 11869 AN: 152090 Hom.: 1373 Cov.: 31 AF XY: 0.0847 AC XY: 6296 AN XY: 74334

African (AFR) AF: 0.121 AC: 5016 AN: 41474

American (AMR) AF: 0.0438 AC: 670 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3470

East Asian (EAS) AF: 0.533 AC: 2749 AN: 5160

South Asian (SAS) AF: 0.264 AC: 1269 AN: 4800

European-Finnish (FIN) AF: 0.0828 AC: 877 AN: 10590

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1033 AN: 67992

Other (OTH) AF: 0.0762 AC: 161 AN: 2114

Alfa AF: 0.0426 Hom.: 2774

Bravo AF: 0.0772

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.114 AC: 504

ESP6500EA AF: 0.0172 AC: 148

ExAC AF: 0.104 AC: 12577

Asia WGS AF: 0.401 AC: 1392 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0140

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Aortic aneurysm, familial thoracic 7 (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	0.27
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.17
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.093
Sift	Benign	0.34	T
Sift4G	Benign	0.45	T
Polyphen		0.0050	B
Vest4		0.060
MutPred		0.23		Gain of sheet (P = 0.1945)
MPC		0.15
ClinPred		0.014	T
GERP RS		-0.82
PromoterAI		0.0066	Neutral
Varity_R		0.022
gMVP		0.044
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: rs3732487; hg19: chr3-123419573; COSMIC: COSV60606227; COSMIC: COSV60606227;