NM_020778.5:c.-66delG

Variant names:

• chr15-84817382-CG-C
• rs974266035
• NM_020778.5:c.-66delG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_020778.5(ALPK3):​c.-66delG 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 0.796

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000239 (36/150698) while in subpopulation AFR AF= 0.000702 (29/41314). AF 95% confidence interval is 0.000501. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5	c.-66delG		5_prime_UTR_variant	Exon 1 of 14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888	c.-66delG		5_prime_UTR_variant	Exon 1 of 14	1	NM_020778.5	ENSP00000258888.6

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 36 AN: 150594 Hom.: 0 Cov.: 33

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

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

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: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy, familial hypertrophic 27 Pathogenic:1

Feb 20, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Nov 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

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

Other links and lift over

dbSNP: rs974266035; hg19: chr15-85360613;