3-123649196-TG-TGG

Variant names:

• chr3-123649196-T-TG
• rs41431347
• NM_053025.4:c.4289-3dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.4289-3dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,605,586 control chromosomes in the GnomAD database, including 1,233 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (98 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1135 hom.)
• Consequence: MYLK NM_053025.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.798
• Publications: 1 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]

LOC124909421 (HGNC:):

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-123649196-T-TG is Benign according to our data. Variant chr3-123649196-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0565 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.4289-3dupC		splice_region intron	N/A	NP_444253.3
	MYLK	NM_053027.4		c.4289-3dupC		splice_region intron	N/A	NP_444255.3
	MYLK	NM_053026.4		c.4082-3dupC		splice_region intron	N/A	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.4289-3_4289-2insC		splice_region intron	N/A	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*3868-3_*3868-2insC		splice_region intron	N/A	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000687848.1		c.4319-3_4319-2insC		splice_region intron	N/A	ENSP00000508761.1	A0A8I5KU53

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5276 AN: 151328 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.00368

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0298

GnomAD2 exomes AF: 0.0351 AC: 8722 AN: 248442 AF XY: 0.0356

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.00496

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0380 AC: 55274 AN: 1454142 Hom.: 1135 Cov.: 33 AF XY: 0.0381 AC XY: 27568 AN XY: 723508

African (AFR) AF: 0.0378 AC: 1252 AN: 33140

American (AMR) AF: 0.0214 AC: 953 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 1713 AN: 26054

East Asian (EAS) AF: 0.00239 AC: 94 AN: 39390

South Asian (SAS) AF: 0.0371 AC: 3189 AN: 86008

European-Finnish (FIN) AF: 0.0255 AC: 1336 AN: 52360

Middle Eastern (MID) AF: 0.0625 AC: 279 AN: 4462

European-Non Finnish (NFE) AF: 0.0400 AC: 44284 AN: 1108172

Other (OTH) AF: 0.0363 AC: 2174 AN: 59966

GnomAD4 genome AF: 0.0349 AC: 5281 AN: 151444 Hom.: 98 Cov.: 32 AF XY: 0.0334 AC XY: 2472 AN XY: 73994

African (AFR) AF: 0.0347 AC: 1433 AN: 41298

American (AMR) AF: 0.0289 AC: 439 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 238 AN: 3452

East Asian (EAS) AF: 0.00330 AC: 17 AN: 5150

South Asian (SAS) AF: 0.0288 AC: 137 AN: 4750

European-Finnish (FIN) AF: 0.0191 AC: 201 AN: 10546

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0401 AC: 2718 AN: 67748

Other (OTH) AF: 0.0295 AC: 62 AN: 2102

Alfa AF: 0.0219 Hom.: 11

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0402

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41431347; hg19: chr3-123368043; COSMIC: COSV60608250; COSMIC: COSV60608250;