rs1555435531
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020778.5(ALPK3):c.3186G>A(p.Trp1062*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020778.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPK3 | NM_020778.5 | c.3186G>A | p.Trp1062* | stop_gained | 6/14 | ENST00000258888.6 | NP_065829.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPK3 | ENST00000258888.6 | c.3186G>A | p.Trp1062* | stop_gained | 6/14 | 1 | NM_020778.5 | ENSP00000258888.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458186Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725300
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiomyopathy, familial hypertrophic 27 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypertrophic cardiomyopathy 27 (MIM#618052). (I) 0106 - This gene is associated with autosomal recessive disease. However, emerging evidence supports autosomal dominant inheritance in adults with age-dependent penetrance (PMIDs: 32480058, 34263907). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. This proband’s family has been previously described in the literature (PMID: 27106955). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. CRISPR/cas9 editing was used to repair one mutant allele in a proband-derived iPSC line, which was sufficient to restore wild-type phenotype. Mutant iPSC presented sarcomeric disorganisation and abnormal intercalated disc morphology, and significantly increased irregular calcium transients (PMID: 27106955). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 12, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at