chr15-84859366-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_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

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0970
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 was made for transcript

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
ALPK3NM_020778.5 linkc.3941G>A p.Arg1314His missense_variant Exon 7 of 14 ENST00000258888.6 NP_065829.4 Q96L96

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALPK3ENST00000258888.6 linkc.3941G>A p.Arg1314His missense_variant Exon 7 of 14 1 NM_020778.5 ENSP00000258888.6 Q96L96

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74322
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

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:1Benign: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
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

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

Other links and lift over

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