15-84817357-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020778.5(ALPK3):c.-96G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,454 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ALPK3 NM_020778.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.102

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05813971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPK3	NM_020778.5	c.-96G>C		5_prime_UTR_variant	1/14	ENST00000258888.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPK3	ENST00000258888.6	c.-96G>C		5_prime_UTR_variant	1/14	1	NM_020778.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151454 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 50

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151454 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73952

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ALPK3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glycine with arginine at codon 171 of the ALPK3 protein (p.Gly171Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.030
Sift	Benign	0.43	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	B
Vest4		0.081
MutPred		0.37		Gain of methylation at G171 (P = 0.0056);
MVP		0.39
MPC		1.3
ClinPred		0.044	T
GERP RS		-1.4
Varity_R		0.086
gMVP		0.17

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: rs1963370921; hg19: chr15-85360588;