rs1555435531

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_020778.5(ALPK3):​c.3186G>A​(p.Trp1062*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.596
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-84857924-G-A is Pathogenic according to our data. Variant chr15-84857924-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 548941.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALPK3NM_020778.5 linkuse as main transcriptc.3186G>A p.Trp1062* stop_gained 6/14 ENST00000258888.6 NP_065829.4 Q96L96

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALPK3ENST00000258888.6 linkuse as main transcriptc.3186G>A p.Trp1062* stop_gained 6/141 NM_020778.5 ENSP00000258888.6 Q96L96

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458186
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725300
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiomyopathy, familial hypertrophic 27 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypertrophic cardiomyopathy 27 (MIM#618052). (I) 0106 - This gene is associated with autosomal recessive disease. However, emerging evidence supports autosomal dominant inheritance in adults with age-dependent penetrance (PMIDs: 32480058, 34263907). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. This proband’s family has been previously described in the literature (PMID: 27106955). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. CRISPR/cas9 editing was used to repair one mutant allele in a proband-derived iPSC line, which was sufficient to restore wild-type phenotype. Mutant iPSC presented sarcomeric disorganisation and abnormal intercalated disc morphology, and significantly increased irregular calcium transients (PMID: 27106955). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 12, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
31
DANN
Uncertain
0.99
Eigen
Uncertain
0.19
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.057
N
Vest4
0.036
GERP RS
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1555435531; hg19: chr15-85401155; API