rs35156360

Variant names:

• chr3-123733085-G-A
• rs35156360
• NM_053025.4:c.1327C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123733085-G-A
• chr3-123733085-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053025.4(MYLK):​c.1327C>T​(p.Pro443Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0171 in 1,613,872 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts 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. P443T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (255 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 5.88
• Publications: 21 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
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=0.007373214).
• BP6: Variant 3-123733085-G-A is Benign according to our data. Variant chr3-123733085-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1863/152256) while in subpopulation NFE AF = 0.0188 (1281/68014). AF 95% confidence interval is 0.018. There are 15 homozygotes in GnomAd4. There are 856 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

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.1327C>T	p.Pro443Ser	missense	Exon 11 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1327C>T	p.Pro443Ser	missense	Exon 11 of 33	NP_444255.3
	MYLK	NM_001321309.2		c.799C>T	p.Pro267Ser	missense	Exon 10 of 33	NP_001308238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.1327C>T	p.Pro443Ser	missense	Exon 11 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*906C>T		non_coding_transcript_exon	Exon 10 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000464489.5	TSL:1	n.*906C>T		3_prime_UTR	Exon 10 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152138 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0141 AC: 3514 AN: 249246 AF XY: 0.0147

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.00774

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00793

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0176 AC: 25769 AN: 1461616 Hom.: 255 Cov.: 35 AF XY: 0.0175 AC XY: 12720 AN XY: 727074

African (AFR) AF: 0.00260 AC: 87 AN: 33478

American (AMR) AF: 0.00790 AC: 353 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 829 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0156 AC: 1342 AN: 86180

European-Finnish (FIN) AF: 0.00800 AC: 427 AN: 53352

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5768

European-Non Finnish (NFE) AF: 0.0193 AC: 21466 AN: 1111916

Other (OTH) AF: 0.0189 AC: 1139 AN: 60390

GnomAD4 genome AF: 0.0122 AC: 1863 AN: 152256 Hom.: 15 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74426

African (AFR) AF: 0.00378 AC: 157 AN: 41560

American (AMR) AF: 0.00836 AC: 128 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4808

European-Finnish (FIN) AF: 0.00622 AC: 66 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1281 AN: 68014

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.0165 Hom.: 95

Bravo AF: 0.0121

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0205 AC: 176

ExAC AF: 0.0144 AC: 1748

EpiCase AF: 0.0206

EpiControl AF: 0.0196

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Aortic aneurysm, familial thoracic 7 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.9
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.58
MPC		0.18
ClinPred		0.034	T
GERP RS		5.4
Varity_R		0.79
gMVP		0.65
Mutation Taster		=95/5	polymorphism

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: rs35156360; hg19: chr3-123451932; COSMIC: COSV60610441; COSMIC: COSV60610441;