3-123682222-ACT-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Moderate
The NM_053025.4(MYLK):c.3652_3652+1del variant causes a splice donor, coding sequence 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.
Frequency
Consequence
NM_053025.4 splice_donor, coding_sequence
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK | NM_053025.4 | c.3652_3652+1del | splice_donor_variant, coding_sequence_variant | 20/34 | ENST00000360304.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK | ENST00000360304.8 | c.3652_3652+1del | splice_donor_variant, coding_sequence_variant | 20/34 | 5 | NM_053025.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1444294Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 716330
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Aortic aneurysm, familial thoracic 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as c.3652_3652+1del. This premature translational stop signal has been observed in individual(s) with aortic dissection (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the MYLK gene. This variant occurs within the aortic-specific isoform of MYLK. Loss-of-function variants in the aortic-specific isoform of MYLK are known to be pathogenic for thoracic aortic dissections (PMID: 21055718). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at