rs12900463

Variant names:

• chr15-84872155-T-C
• rs12900463
• NM_020778.5:c.*3699T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020778.5(ALPK3):​c.*3699T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,276 control chromosomes in the GnomAD database, including 2,831 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2830 hom., cov: 34)
  • Exomes 𝑓: 0.16 (1 hom.)
• Consequence: ALPK3 NM_020778.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538
• Publications: 16 publications found

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]

ALPK3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cardiomyopathy, familial hypertrophic 27

  Inheritance: AR, AD, SD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5	c.*3699T>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6	c.*3699T>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_020778.5	ENSP00000258888.6

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26007 AN: 152108 Hom.: 2833 Cov.: 34

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.160 AC: 8 AN: 50 Hom.: 1 Cov.: 0 AF XY: 0.190 AC XY: 8 AN XY: 42

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.174 AC: 8 AN: 46

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.171 AC: 25998 AN: 152226 Hom.: 2830 Cov.: 34 AF XY: 0.171 AC XY: 12722 AN XY: 74420

African (AFR) AF: 0.0420 AC: 1743 AN: 41546

American (AMR) AF: 0.200 AC: 3067 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 816 AN: 3468

East Asian (EAS) AF: 0.130 AC: 674 AN: 5180

South Asian (SAS) AF: 0.151 AC: 729 AN: 4828

European-Finnish (FIN) AF: 0.261 AC: 2760 AN: 10594

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15495 AN: 67992

Other (OTH) AF: 0.196 AC: 414 AN: 2112

Alfa AF: 0.214 Hom.: 6807

Bravo AF: 0.163

Asia WGS AF: 0.146 AC: 507 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.4
DANN	Benign	0.41
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12900463; hg19: chr15-85415386;