Genetic Variant ALPK3:c.-89C>T (chr15-84817364-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020778.5(ALPK3):c.-89C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,076,854 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: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.496

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]

ALPK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24379897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5 link	c.-89C>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000258888.6	NP_065829.4	Q96L96

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6 link	c.-89C>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_020778.5	ENSP00000258888.6		Q96L96

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1076854

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

509812

show subpopulations

African (AFR)

AF:

0.0000891

AC:

AN:

22440

American (AMR)

AF:

0.00

AC:

AN:

8030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13860

East Asian (EAS)

AF:

0.00

AC:

AN:

25546

South Asian (SAS)

AF:

0.00

AC:

AN:

20482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2870

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

919246

Other (OTH)

AF:

0.00

AC:

AN:

43064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Apr 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A173V variant (also known as c.518C>T), located in coding exon 1 of the ALPK3 gene, results from a C to T substitution at nucleotide position 518. The alanine at codon 173 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.50

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.49

REVEL

Benign

0.11

Sift

Uncertain

0.014

Sift4G

Benign

0.071

Polyphen

0.95

Vest4

0.13

MutPred

0.41

Gain of sheet (P = 0.0061);

MVP

0.64

MPC

1.1

ClinPred

0.36

GERP RS

1.4

PromoterAI

-0.16

Neutral

(source)

Varity_R

0.050

gMVP

0.074

Mutation Taster

=97/3

polymorphism

(source)

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

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15-84817364-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over