Genetic Variant ALPK3:c.-66G>A (chr15-84817387-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020778.5(ALPK3):c.-66G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 1,219,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

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]

ALPK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11216271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5 link	c.-66G>A		5_prime_UTR_variant	Exon 1 of 14	ENST00000258888.6	NP_065829.4	Q96L96

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6 link	c.-66G>A		5_prime_UTR_variant	Exon 1 of 14	1	NM_020778.5	ENSP00000258888.6		Q96L96

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151182

Hom.:

Cov.:

show subpopulations

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

AF:

0.00000281

AC:

AN:

1068812

Hom.:

Cov.:

AF XY:

0.00000198

AC XY:

AN XY:

505996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22072

American (AMR)

AF:

0.00

AC:

AN:

7698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13360

East Asian (EAS)

AF:

0.00

AC:

AN:

24486

South Asian (SAS)

AF:

0.00

AC:

AN:

20430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2834

European-Non Finnish (NFE)

AF:

0.00000219

AC:

AN:

914390

Other (OTH)

AF:

0.0000236

AC:

AN:

42440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73818

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67728

Other (OTH)

AF:

0.00

AC:

AN:

2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0051

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.34

M_CAP

Benign

0.040

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.25

REVEL

Benign

0.088

Sift

Benign

0.15

Sift4G

Benign

0.18

Polyphen

0.20

Vest4

0.12

MutPred

0.26

Gain of phosphorylation at A181 (P = 0.035);

MVP

0.50

MPC

1.0

ClinPred

0.18

GERP RS

2.5

PromoterAI

0.11

Neutral

(source)

Varity_R

0.045

gMVP

0.081

Mutation Taster

=92/8

polymorphism

(source)

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

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chr15-84817387-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over