NM_020778.5:c.-90G>A

Variant names:

• chr15-84817363-G-A
• rs1441192383
• NM_020778.5:c.-90G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020778.5(ALPK3):​c.-90G>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 0.0000171 in 1,229,022 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ALPK3 NM_020778.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.49
• Publications: 0 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, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen
• cardiomyopathy, familial hypertrophic 27

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21584976).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020778.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	NM_020778.5	MANE Select	c.-90G>A		5_prime_UTR	Exon 1 of 14	NP_065829.4	Q96L96

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	ENST00000258888.6	TSL:1 MANE Select	c.-90G>A		5_prime_UTR	Exon 1 of 14	ENSP00000258888.6	Q96L96
	ALPK3	ENST00000934403.1		c.-90G>A		5_prime_UTR	Exon 1 of 13	ENSP00000604462.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151310 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 19 AN: 1077712 Hom.: 0 Cov.: 50 AF XY: 0.0000157 AC XY: 8 AN XY: 510274

African (AFR) AF: 0.00 AC: 0 AN: 22452

American (AMR) AF: 0.00 AC: 0 AN: 8046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13888

East Asian (EAS) AF: 0.00 AC: 0 AN: 25560

South Asian (SAS) AF: 0.00 AC: 0 AN: 20586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2872

European-Non Finnish (NFE) AF: 0.0000196 AC: 18 AN: 919846

Other (OTH) AF: 0.0000232 AC: 1 AN: 43120

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151310 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73856

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67728

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.063
Sift	Uncertain	0.015	D
Sift4G	Benign	0.12	T
Polyphen		0.76	P
Vest4		0.10
MutPred		0.34		Loss of helix (P = 0.0068)
MVP		0.53
MPC		1.0
ClinPred		0.31	T
GERP RS		2.5
PromoterAI		-0.031	Neutral
Varity_R		0.083
gMVP		0.084
Mutation Taster		=99/1	polymorphism

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: rs1441192383; hg19: chr15-85360594;