rs576620371

Variant names:

• chr3-123667194-CAAA-C
• rs576620371
• NM_053025.4:c.3653-10_3653-8delTTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_053025.4(MYLK):​c.3653-10_3653-8delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: MYLK NM_053025.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.78
• Publications: 0 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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 3-123667194-CAAA-C is Benign according to our data. Variant chr3-123667194-CAAA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471725.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152284) while in subpopulation AMR AF = 0.00085 (13/15300). AF 95% confidence interval is 0.000502. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.3653-10_3653-8delTTT		splice_region intron	N/A	NP_444253.3
	MYLK	NM_053027.4		c.3653-10_3653-8delTTT		splice_region intron	N/A	NP_444255.3
	MYLK	NM_053026.4		c.3446-10_3446-8delTTT		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.3653-10_3653-8delTTT		splice_region intron	N/A	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*3232-10_*3232-8delTTT		splice_region intron	N/A	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000687848.1		c.3683-10_3683-8delTTT		splice_region intron	N/A	ENSP00000508761.1	A0A8I5KU53

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000322 AC: 81 AN: 251296 AF XY: 0.000265

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461736 Hom.: 1 AF XY: 0.000334 AC XY: 243 AN XY: 727182

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000738 AC: 33 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000365 AC: 406 AN: 1111872

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152284 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000257

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Aortic aneurysm, familial thoracic 7 (1)
-	-	1	MYLK-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs576620371; hg19: chr3-123386041;