rs4678047

Variant names:

• chr3-123733991-G-A
• rs4678047
• NM_053025.4:c.1005C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123733991-G-A
• chr3-123733991-G-C
• chr3-123733991-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):​c.1005C>T​(p.Thr335Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,613,908 control chromosomes in the GnomAD database, including 352,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28815 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323751 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.12
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-123733991-G-A is Benign according to our data. Variant chr3-123733991-G-A is described in ClinVar as Benign. ClinVar VariationId is 226753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 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.1005C>T	p.Thr335Thr	synonymous	Exon 10 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1005C>T	p.Thr335Thr	synonymous	Exon 10 of 33	NP_444255.3
	MYLK	NM_053026.4		c.1005C>T	p.Thr335Thr	synonymous	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.1005C>T	p.Thr335Thr	synonymous	Exon 10 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*584C>T		non_coding_transcript_exon	Exon 9 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000464489.5	TSL:1	n.*584C>T		3_prime_UTR	Exon 9 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91243 AN: 151924 Hom.: 28807 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.663 AC: 164937 AN: 248802 AF XY: 0.661

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.662 AC: 967868 AN: 1461866 Hom.: 323751 Cov.: 90 AF XY: 0.661 AC XY: 480420 AN XY: 727228

African (AFR) AF: 0.387 AC: 12942 AN: 33478

American (AMR) AF: 0.703 AC: 31425 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 16707 AN: 26136

East Asian (EAS) AF: 0.943 AC: 37428 AN: 39698

South Asian (SAS) AF: 0.604 AC: 52135 AN: 86246

European-Finnish (FIN) AF: 0.645 AC: 34448 AN: 53416

Middle Eastern (MID) AF: 0.598 AC: 3449 AN: 5764

European-Non Finnish (NFE) AF: 0.665 AC: 739492 AN: 1112008

Other (OTH) AF: 0.660 AC: 39842 AN: 60396

GnomAD4 genome AF: 0.600 AC: 91274 AN: 152042 Hom.: 28815 Cov.: 32 AF XY: 0.604 AC XY: 44908 AN XY: 74316

African (AFR) AF: 0.399 AC: 16535 AN: 41458

American (AMR) AF: 0.697 AC: 10655 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2236 AN: 3468

East Asian (EAS) AF: 0.940 AC: 4834 AN: 5144

South Asian (SAS) AF: 0.610 AC: 2936 AN: 4816

European-Finnish (FIN) AF: 0.630 AC: 6665 AN: 10586

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45218 AN: 67964

Other (OTH) AF: 0.647 AC: 1366 AN: 2112

Alfa AF: 0.642 Hom.: 37259

Bravo AF: 0.600

Asia WGS AF: 0.738 AC: 2566 AN: 3478

EpiCase AF: 0.666

EpiControl AF: 0.665

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Aortic aneurysm, familial thoracic 7 (4)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Megacystis, microcolon, hypoperistalsis syndrome (1)
-	-	1	MYLK-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.76
PhyloP100		1.1
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: rs4678047; hg19: chr3-123452838; COSMIC: COSV100659259; COSMIC: COSV100659259;