rs762110595
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_020778.5(ALPK3):c.4130-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 1,603,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_020778.5 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPK3 | NM_020778.5 | c.4130-1G>A | splice_acceptor_variant | ENST00000258888.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPK3 | ENST00000258888.6 | c.4130-1G>A | splice_acceptor_variant | 1 | NM_020778.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247376Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133654
GnomAD4 exome AF: 0.00000896 AC: 13AN: 1451062Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9AN XY: 719924
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This variant is present in population databases (rs762110595, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 9 of the ALPK3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Disruption of this splice site has been observed in individual(s) with severe pediatric cardiomyopathy (PMID: 26846950). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10 and introduces a premature termination codon (PMID: 26846950). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 548939). - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiomyopathy, familial hypertrophic 27 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 03, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at