GeneBe

rs758966808

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BS1_Supporting

The NM_053025.4(MYLK):​c.3096_3131delTGAGACCCTGAAGCCAATGGGCAACGCCAAGCCTGC​(p.Glu1033_Ala1044del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 151,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000055 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MYLK
NM_053025.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.04
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_053025.4.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000238 (36/151568) while in subpopulation AFR AF= 0.000728 (30/41226). AF 95% confidence interval is 0.000524. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYLKNM_053025.4 linkc.3096_3131delTGAGACCCTGAAGCCAATGGGCAACGCCAAGCCTGC p.Glu1033_Ala1044del disruptive_inframe_deletion Exon 18 of 34 ENST00000360304.8 NP_444253.3 Q15746-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYLKENST00000360304.8 linkc.3096_3131delTGAGACCCTGAAGCCAATGGGCAACGCCAAGCCTGC p.Glu1033_Ala1044del disruptive_inframe_deletion Exon 18 of 34 5 NM_053025.4 ENSP00000353452.3 Q15746-1

Frequencies

GnomAD3 genomes
AF:
0.000238
AC:
36
AN:
151568
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000728
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251462
Hom.:
0
AF XY:
0.000132
AC XY:
18
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000547
AC:
80
AN:
1461830
Hom.:
0
AF XY:
0.0000578
AC XY:
42
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000238
AC:
36
AN:
151568
Hom.:
0
Cov.:
30
AF XY:
0.000270
AC XY:
20
AN XY:
73964
show subpopulations
Gnomad4 AFR
AF:
0.000728
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000192
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 7 Uncertain:1
Dec 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.3096_3131del, results in the deletion of 12 amino acid(s) of the MYLK protein (p.Ala1044_Pro1055del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758966808, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 471716). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Jan 22, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3096_3131del36 variant (also known as p.A1044_P1055DEL) is located in coding exon 15 of the MYLK gene. This variant results from an in-frame deletion of 36 nucleotides at positions 3096 to 3131. This results in the deletion of 12 amino acids between codons 1044 and 1055. Based on data from gnomAD, the in-frame deletion has an overall frequency of approximately 0.011% (32/282778). Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear. -

Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 Uncertain:1
Aug 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
May 30, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In-frame deletion of 12 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on protein structure/function -

MYLK-related disorder Uncertain:1
Dec 27, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MYLK c.3096_3131del36 variant is predicted to result in an in-frame deletion (p.Ala1044_Pro1055del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs758966808; hg19: chr3-123419183; API