3-123739964-G-C

Variant names:

• chr3-123739964-G-C
• rs55760507
• NM_053025.4:c.411C>G

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.411C>G​(p.Ser137Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,613,896 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S137S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (289 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (249 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.08
• Publications: 4 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=-0.57).
• BP6: Variant 3-123739964-G-C is Benign according to our data. Variant chr3-123739964-G-C is described in ClinVar as Benign. ClinVar VariationId is 226766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.411C>G	p.Ser137Ser	synonymous	Exon 6 of 34	NP_444253.3
	MYLK	NM_053027.4		c.411C>G	p.Ser137Ser	synonymous	Exon 6 of 33	NP_444255.3
	MYLK	NM_053026.4		c.411C>G	p.Ser137Ser	synonymous	Exon 6 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.411C>G	p.Ser137Ser	synonymous	Exon 6 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.203C>G		non_coding_transcript_exon	Exon 5 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000687848.1		c.441C>G	p.Ser147Ser	synonymous	Exon 4 of 32	ENSP00000508761.1	A0A8I5KU53

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5061 AN: 152162 Hom.: 278 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0106 AC: 2671 AN: 251442 AF XY: 0.00827

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00971

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.00485 AC: 7083 AN: 1461616 Hom.: 249 Cov.: 31 AF XY: 0.00452 AC XY: 3287 AN XY: 727112

African (AFR) AF: 0.111 AC: 3707 AN: 33474

American (AMR) AF: 0.0116 AC: 520 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 502 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86218

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5766

European-Non Finnish (NFE) AF: 0.00142 AC: 1574 AN: 1111820

Other (OTH) AF: 0.0107 AC: 645 AN: 60380

GnomAD4 genome AF: 0.0336 AC: 5114 AN: 152280 Hom.: 289 Cov.: 33 AF XY: 0.0320 AC XY: 2382 AN XY: 74468

African (AFR) AF: 0.111 AC: 4596 AN: 41546

American (AMR) AF: 0.0167 AC: 256 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68028

Other (OTH) AF: 0.0332 AC: 70 AN: 2110

Alfa AF: 0.0126 Hom.: 24

Bravo AF: 0.0396

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.6
DANN	Benign	0.91
PhyloP100		2.1
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: rs55760507; hg19: chr3-123458811;