chr15-84859366-G-A

Variant names:

• chr15-84859366-G-A
• rs746125587
• NM_020778.5:c.3941G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_020778.5(ALPK3):​c.3941G>A​(p.Arg1314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1314C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ALPK3 NM_020778.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.0970

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069767833).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000041 (60/1461844) while in subpopulation AMR AF = 0.000939 (42/44720). AF 95% confidence interval is 0.000714. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. 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.3941G>A	p.Arg1314His	missense_variant	Exon 7 of 14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6	c.3941G>A	p.Arg1314His	missense_variant	Exon 7 of 14	1	NM_020778.5	ENSP00000258888.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251278 AF XY: 0.000125

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727224

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111986

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1516 of the ALPK3 protein (p.Arg1516His). This variant is present in population databases (rs746125587, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALPK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510476). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ALPK3 protein function with a negative predictive value of 80%. 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. -

May 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Cardiovascular phenotype Uncertain:1 Benign:1

Oct 29, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2;BP1;BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.8
DANN	Benign	0.86
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.097
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.051
Sift	Benign	0.68	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.39		Gain of methylation at K1513 (P = 0.0861);
MVP		0.21
MPC		0.14
ClinPred		0.019	T
GERP RS		-0.84
Varity_R		0.017
gMVP		0.13
Mutation Taster		=96/4	polymorphism

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: rs746125587; hg19: chr15-85402597; COSMIC: COSV104579884; COSMIC: COSV104579884;