chr3-123734214-A-G

Variant names:

• chr3-123734214-A-G
• rs3796164
• NM_053025.4:c.782T>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.782T>C​(p.Val261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,537,270 control chromosomes in the GnomAD database, including 14,158 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (4698 hom., cov: 31)
  • Exomes 𝑓: 0.048 (9460 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.145
• Publications: 23 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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.8411875E-4).
• BP6: Variant 3-123734214-A-G is Benign according to our data. Variant chr3-123734214-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 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.782T>C	p.Val261Ala	missense	Exon 10 of 34	NP_444253.3
	MYLK	NM_053027.4		c.782T>C	p.Val261Ala	missense	Exon 10 of 33	NP_444255.3
	MYLK	NM_053026.4		c.782T>C	p.Val261Ala	missense	Exon 10 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.782T>C	p.Val261Ala	missense	Exon 10 of 34	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.*361T>C		non_coding_transcript_exon	Exon 9 of 33	ENSP00000417798.1
	MYLK	ENST00000464489.5	TSL:1	n.*361T>C		3_prime_UTR	Exon 9 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23686 AN: 150974 Hom.: 4677 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.116 AC: 21447 AN: 184602 AF XY: 0.107

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0476 AC: 66050 AN: 1386180 Hom.: 9460 Cov.: 47 AF XY: 0.0505 AC XY: 34525 AN XY: 683824

African (AFR) AF: 0.448 AC: 13906 AN: 31008

American (AMR) AF: 0.0544 AC: 1919 AN: 35270

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 859 AN: 22008

East Asian (EAS) AF: 0.421 AC: 16478 AN: 39102

South Asian (SAS) AF: 0.210 AC: 15483 AN: 73900

European-Finnish (FIN) AF: 0.0233 AC: 863 AN: 37092

Middle Eastern (MID) AF: 0.0560 AC: 295 AN: 5272

European-Non Finnish (NFE) AF: 0.0104 AC: 11291 AN: 1085092

Other (OTH) AF: 0.0863 AC: 4956 AN: 57436

GnomAD4 genome AF: 0.157 AC: 23762 AN: 151090 Hom.: 4698 Cov.: 31 AF XY: 0.158 AC XY: 11692 AN XY: 73812

African (AFR) AF: 0.435 AC: 17782 AN: 40874

American (AMR) AF: 0.0715 AC: 1089 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2273 AN: 5044

South Asian (SAS) AF: 0.247 AC: 1171 AN: 4748

European-Finnish (FIN) AF: 0.0227 AC: 238 AN: 10502

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 770 AN: 67928

Other (OTH) AF: 0.132 AC: 276 AN: 2092

Alfa AF: 0.0635 Hom.: 6057

Bravo AF: 0.173

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.433 AC: 1910

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.111 AC: 13342

Asia WGS AF: 0.372 AC: 1293 AN: 3478

ClinVar

ClinVar submissions as Germline

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	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.45
DANN	Benign	0.81
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.14
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.064
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.050
MPC		0.50
ClinPred		0.0063	T
GERP RS		-0.086
Varity_R		0.042
gMVP		0.12
Mutation Taster		=99/1	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: rs3796164; hg19: chr3-123453061; COSMIC: COSV60609998; COSMIC: COSV60609998;