chr15-84857913-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020778.5(ALPK3):c.3175C>T(p.Arg1059*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,610,920 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
ALPK3
NM_020778.5 stop_gained
NM_020778.5 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 2.66
Genes affected
ALPK3 (HGNC:17574): (alpha kinase 3) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 15-84857913-C-T is Pathogenic according to our data. Variant chr15-84857913-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-84857913-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000416 AC: 10AN: 240334Hom.: 0 AF XY: 0.0000305 AC XY: 4AN XY: 131030
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GnomAD4 exome AF: 0.0000754 AC: 110AN: 1458712Hom.: 0 Cov.: 30 AF XY: 0.0000717 AC XY: 52AN XY: 725530
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GnomAD4 genome 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy, familial hypertrophic 27 Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 03, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 23, 2021 | The ALPK3 c.3175C>T, p.Arg1059Ter variant (rs749465164) is reported homozygous in the literature in a family with severe pediatric cardiomyopathy and heterozygous in the asymptomatic parents (Almomani 2016). This variant is reported in ClinVar (Variation ID: 488984). This variant is found in the non-Finnish European population with an allele frequency of 0.008% (9/107310 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Almomani R et al. Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. J Am Coll Cardiol. 2016 Feb 9;67(5):515-25. PMID: 26846950. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | 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) 0108 - This gene is associated with both recessive and dominant disease (PMID: 34263907). (I) 0112 - The condition associated with this gene has incomplete penetrance. Age-dependent penetrance has been observed in the autosomal dominant condition (PMID: 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) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported in ClinVar as pathogenic in individuals with cardiomyopathy. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with cardiomyopathy (ClinVar, PMID: 26846950). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant has also been shown to segregate with disease in three affected siblings from one family (PMID: 26846950). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg1261*) in the ALPK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPK3 are known to be pathogenic (PMID: 21441111, 26846950, 27106955, 34263907). This variant is present in population databases (rs749465164, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ALPK3-related conditions (PMID: 26846950). ClinVar contains an entry for this variant (Variation ID: 488984). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27106955, 28630369, 26846950, 32480058, 31216405, 34263907, 39036505, 29661763) - |
Neurodevelopmental disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jan 19, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2022 | The p.R1261* pathogenic mutation (also known as c.3781C>T), located in coding exon 6 of the ALPK3 gene, results from a C to T substitution at nucleotide position 3781. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been reported in the homozygous state in three siblings of unaffected, consanguineous parents. Two siblings were diagnosed with severe cardiomyopathy and hydrops fetalis in utero, and one was diagnosed with severe concentric left ventricular hypertrophy at birth. An unaffected sibling and the father were heterozygous for the variant (Almomani R et al. J. Am. Coll. Cardiol., 2016 Feb;67:515-25). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
ALPK3-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 13, 2023 | The ALPK3 c.3781C>T variant is predicted to result in premature protein termination (p.Arg1261*). This variant has been reported in the homozygous state in individuals with congenital cardiomyopathy (see for example - Almomani et al. 2016. PubMed ID: 26846950; Table S2, van Velzen et al. 2018. PubMed ID: 29661763). This variant is reported in 0.0084% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-85401144-C-T). Nonsense variants in ALPK3 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at