15-84817376-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020778.5(ALPK3):c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,220,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000019 ( 0 hom. )
Consequence
ALPK3
NM_020778.5 5_prime_UTR
NM_020778.5 5_prime_UTR
Scores
1
1
17
Clinical Significance
Conservation
PhyloP100: 0.538
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.084248155).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPK3 | NM_020778.5 | c.-77G>A | 5_prime_UTR_variant | 1/14 | ENST00000258888.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPK3 | ENST00000258888.6 | c.-77G>A | 5_prime_UTR_variant | 1/14 | 1 | NM_020778.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151200Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000187 AC: 2AN: 1069006Hom.: 0 Cov.: 50 AF XY: 0.00000198 AC XY: 1AN XY: 505806
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GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151200Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 73812
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2017 | A variant of uncertain significance has been identified in the ALPK3 gene. The R177K variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R177K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2022 | The p.R177K variant (also known as c.530G>A), located in coding exon 1 of the ALPK3 gene, results from a G to A substitution at nucleotide position 530. The arginine at codon 177 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of glycosylation at R177 (P = 0.0053);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at