chr15-84817382-CG-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020778.5(ALPK3):​c.-66del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,218,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.796
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALPK3NM_020778.5 linkuse as main transcriptc.-66del 5_prime_UTR_variant 1/14 ENST00000258888.6 NP_065829.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALPK3ENST00000258888.6 linkuse as main transcriptc.-66del 5_prime_UTR_variant 1/141 NM_020778.5 ENSP00000258888 P1

Frequencies

GnomAD3 genomes
AF:
0.000239
AC:
36
AN:
150594
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000704
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000661
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0160
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000484
GnomAD4 exome
AF:
0.0000168
AC:
18
AN:
1068288
Hom.:
0
Cov.:
49
AF XY:
0.0000277
AC XY:
14
AN XY:
505556
show subpopulations
Gnomad4 AFR exome
AF:
0.000679
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000109
Gnomad4 OTH exome
AF:
0.0000471
GnomAD4 genome
AF:
0.000239
AC:
36
AN:
150698
Hom.:
0
Cov.:
33
AF XY:
0.000204
AC XY:
15
AN XY:
73642
show subpopulations
Gnomad4 AFR
AF:
0.000702
Gnomad4 AMR
AF:
0.0000660
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000193

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This sequence change creates a premature translational stop signal (p.Ala181Profs*130) in the ALPK3 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 203 has the potential to rescue this truncating variant. This variant is present in population databases (no rsID available, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of ALPK3-related conditions (PMID: 32480058). ClinVar contains an entry for this variant (Variation ID: 1487747). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 28, 2023The c.541delG variant, located in coding exon 1 of the ALPK3 gene, results from a deletion of one nucleotide at nucleotide position 541, causing a translational frameshift with a predicted alternate stop codon (p.A181Pfs*130). This variant was reported in one individual with dilated cardiomyopathy, who had a second ALPK3 variant also detected; however, phase information was not provided (Herkert JC et al. Am Heart J, 2020 07;225:108-119). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, based on data from gnomAD, several loss of function alterations in the first exon of ALPK3 (p.C64* and p.E148Qfs*8) are too frequent to cause disease given the incidence of pediatric cardiomyopathy. The abundance of nonsense and frameshift alleles in the first exon in population databases brings into question the pathogenicity of loss of function alterations in N-terminus of ALPK3 and suggests the possibility of an alternative start site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs974266035; hg19: chr15-85360613; API