3-123700886-A-G

Variant names:

• chr3-123700886-A-G
• rs3732486
• NM_053025.4:c.2582T>C

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.2582T>C​(p.Leu861Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,612,728 control chromosomes in the GnomAD database, including 12,902 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L861L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (2716 hom., cov: 31)
  • Exomes 𝑓: 0.055 (10186 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.35
• Publications: 16 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=1.2800097E-4).
• BP6: Variant 3-123700886-A-G is Benign according to our data. Variant chr3-123700886-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 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.2582T>C	p.Leu861Pro	missense	Exon 18 of 34	NP_444253.3
	MYLK	NM_053027.4		c.2582T>C	p.Leu861Pro	missense	Exon 18 of 33	NP_444255.3
	MYLK	NM_053026.4		c.2375T>C	p.Leu792Pro	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.2582T>C	p.Leu861Pro	missense	Exon 18 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000504946.6	TSL:1	c.191T>C	p.Leu64Pro	missense	Exon 2 of 4	ENSP00000510315.1	A0A8I5KYZ0
	MYLK	ENST00000464489.5	TSL:1	n.*2161T>C		non_coding_transcript_exon	Exon 17 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18666 AN: 151820 Hom.: 2698 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.115 AC: 28763 AN: 249654 AF XY: 0.116

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.0615

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.562

Gnomad FIN exome AF: 0.0760

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0547 AC: 79948 AN: 1460790 Hom.: 10186 Cov.: 40 AF XY: 0.0595 AC XY: 43229 AN XY: 726770

African (AFR) AF: 0.282 AC: 9429 AN: 33480

American (AMR) AF: 0.0607 AC: 2713 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 686 AN: 26136

East Asian (EAS) AF: 0.483 AC: 19175 AN: 39700

South Asian (SAS) AF: 0.247 AC: 21300 AN: 86258

European-Finnish (FIN) AF: 0.0717 AC: 3754 AN: 52346

Middle Eastern (MID) AF: 0.0461 AC: 266 AN: 5768

European-Non Finnish (NFE) AF: 0.0154 AC: 17156 AN: 1111998

Other (OTH) AF: 0.0906 AC: 5469 AN: 60380

GnomAD4 genome AF: 0.123 AC: 18731 AN: 151938 Hom.: 2716 Cov.: 31 AF XY: 0.128 AC XY: 9523 AN XY: 74248

African (AFR) AF: 0.276 AC: 11441 AN: 41422

American (AMR) AF: 0.0616 AC: 942 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.534 AC: 2724 AN: 5102

South Asian (SAS) AF: 0.269 AC: 1296 AN: 4812

European-Finnish (FIN) AF: 0.0837 AC: 884 AN: 10566

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0162 AC: 1100 AN: 67966

Other (OTH) AF: 0.111 AC: 235 AN: 2110

Alfa AF: 0.0699 Hom.: 946

Bravo AF: 0.128

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.260 AC: 1145

ESP6500EA AF: 0.0179 AC: 154

ExAC AF: 0.120 AC: 14519

Asia WGS AF: 0.412 AC: 1430 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0152

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	0.26
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.13
Sift	Benign	0.94	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.16
MPC		0.26
ClinPred		0.0044	T
GERP RS		4.8
PromoterAI		0.049	Neutral
Varity_R		0.12
gMVP		0.14
Mutation Taster		=98/2	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: rs3732486; hg19: chr3-123419733; COSMIC: COSV60606243; COSMIC: COSV60606243;