chr3-123682222-ACT-A
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_053025.4(MYLK):c.3652_3652+1delAG(p.Ser1218fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1218S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
MYLK
NM_053025.4 frameshift, splice_donor, splice_region, intron
NM_053025.4 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.33
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]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-123682222-ACT-A is Pathogenic according to our data. Variant chr3-123682222-ACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 471724.Status of the report is criteria_provided_single_submitter, 1 stars.
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.3652_3652+1delAG | p.Ser1218fs | frameshift splice_donor splice_region intron | Exon 20 of 34 | NP_444253.3 | ||
| MYLK | NM_053027.4 | c.3652_3652+1delAG | p.Ser1218fs | frameshift splice_donor splice_region intron | Exon 20 of 33 | NP_444255.3 | |||
| MYLK | NM_053026.4 | c.3445_3445+1delAG | p.Ser1149fs | frameshift splice_donor splice_region intron | Exon 19 of 33 | NP_444254.3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MYLK | ENST00000504946.6 | TSL:1 | c.1261_1262delAG | p.Ser421fs | frameshift | Exon 4 of 4 | ENSP00000510315.1 | ||
| MYLK | ENST00000360304.8 | TSL:5 MANE Select | c.3652_3652+1delAG | p.Ser1218fs | frameshift splice_donor splice_region intron | Exon 20 of 34 | ENSP00000353452.3 | ||
| MYLK | ENST00000464489.5 | TSL:1 | n.*3231_*3231+1delAG | splice_region non_coding_transcript_exon | Exon 19 of 33 | ENSP00000417798.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1444294Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 716330 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1444294
Hom.:
AF XY:
AC XY:
0
AN XY:
716330
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33344
American (AMR)
AF:
AC:
0
AN:
41982
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25640
East Asian (EAS)
AF:
AC:
0
AN:
39340
South Asian (SAS)
AF:
AC:
0
AN:
82710
European-Finnish (FIN)
AF:
AC:
0
AN:
52372
Middle Eastern (MID)
AF:
AC:
0
AN:
5744
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1103332
Other (OTH)
AF:
AC:
0
AN:
59830
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
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0
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1
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2
0.00
0.20
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0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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<30
30-35
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Aortic aneurysm, familial thoracic 7 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 4
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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