chr3-123700935-G-A

Variant names:

• chr3-123700935-G-A
• rs3732485
• NM_053025.4:c.2533C>T

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.2533C>T​(p.Arg845Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,056 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R845H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (62 hom., cov: 30)
  • Exomes 𝑓: 0.012 (586 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0490
• Publications: 13 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=0.0014624298).
• BP6: Variant 3-123700935-G-A is Benign according to our data. Variant chr3-123700935-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0789 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.2533C>T	p.Arg845Cys	missense	Exon 18 of 34	NP_444253.3
	MYLK	NM_053027.4		c.2533C>T	p.Arg845Cys	missense	Exon 18 of 33	NP_444255.3
	MYLK	NM_053026.4		c.2326C>T	p.Arg776Cys	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.2533C>T	p.Arg845Cys	missense	Exon 18 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000504946.6	TSL:1	c.142C>T	p.Arg48Cys	missense	Exon 2 of 4	ENSP00000510315.1	A0A8I5KYZ0
	MYLK	ENST00000464489.5	TSL:1	n.*2112C>T		non_coding_transcript_exon	Exon 17 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2477 AN: 152010 Hom.: 62 Cov.: 30

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0856

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0270 AC: 6650 AN: 246212 AF XY: 0.0293

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.00331

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0117 AC: 17118 AN: 1458928 Hom.: 586 Cov.: 39 AF XY: 0.0140 AC XY: 10192 AN XY: 725962

African (AFR) AF: 0.0157 AC: 525 AN: 33480

American (AMR) AF: 0.0269 AC: 1204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26136

East Asian (EAS) AF: 0.0398 AC: 1579 AN: 39700

South Asian (SAS) AF: 0.0871 AC: 7511 AN: 86258

European-Finnish (FIN) AF: 0.0535 AC: 2704 AN: 50502

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.00225 AC: 2506 AN: 1111990

Other (OTH) AF: 0.0154 AC: 931 AN: 60370

GnomAD4 genome AF: 0.0163 AC: 2484 AN: 152128 Hom.: 62 Cov.: 30 AF XY: 0.0200 AC XY: 1490 AN XY: 74344

African (AFR) AF: 0.0164 AC: 680 AN: 41512

American (AMR) AF: 0.0116 AC: 178 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.0481 AC: 247 AN: 5132

South Asian (SAS) AF: 0.0857 AC: 413 AN: 4818

European-Finnish (FIN) AF: 0.0660 AC: 699 AN: 10588

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68008

Other (OTH) AF: 0.0142 AC: 30 AN: 2106

Alfa AF: 0.00688 Hom.: 3

Bravo AF: 0.0117

ESP6500AA AF: 0.0139 AC: 61

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.0265 AC: 3213

Asia WGS AF: 0.0750 AC: 259 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Aortic aneurysm, familial thoracic 7 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Aortic aneurysm, familial thoracic 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.049
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.062
Sift	Benign	0.25	T
Sift4G	Benign	0.10	T
Polyphen		0.021	B
Vest4		0.083
MPC		0.22
ClinPred		0.0016	T
GERP RS		1.3
PromoterAI		-0.057	Neutral
Varity_R		0.048
gMVP		0.21
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: rs3732485; hg19: chr3-123419782; COSMIC: COSV60619931; COSMIC: COSV60619931;