rs1555436118

Positions:

• chr15-84864630-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000258888.6(ALPK3):​c.4688G>A​(p.Trp1563Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ALPK3 ENST00000258888.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.37

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 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 15-84864630-G-A is Pathogenic according to our data. Variant chr15-84864630-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 548940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-84864630-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPK3	NM_020778.5	c.4688G>A	p.Trp1563Ter	stop_gained	12/14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6	c.4688G>A	p.Trp1563Ter	stop_gained	12/14	1	NM_020778.5	ENSP00000258888	P1
ALPK3	ENST00000558077.1	n.301G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy, familial hypertrophic 27 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 03, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2022

The p.W1765* pathogenic mutation (also known as c.5294G>A), located in coding exon 12 of the ALPK3 gene, results from a G to A substitution at nucleotide position 5294. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This alteration was reported as homozygous in a four-year-old subject with hypertrophic cardiomyopathy (HCM) and as heterozygous in the father who was diagnosed with HCM in adulthood (Almomani R et al. J Am Coll Cardiol, 2016 Feb;67:515-25). This alteration has also been reported as homozygous in several family members with dilated cardiomyopathy and hypertrophic cardiomyopathy phenotypes (Al Senaidi K et al. Am J Med Genet A, 2019 07;179:1235-1240). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.15
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555436118; hg19: chr15-85407861;