15-84858449-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020778.5(ALPK3):c.3711C>T(p.Asp1237=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 1,566,998 control chromosomes in the GnomAD database, including 3,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (355 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3056 hom.)
• Consequence: ALPK3 NM_020778.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.852

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-84858449-C-T is Benign according to our data. Variant chr15-84858449-C-T is described in ClinVar as [Benign]. Clinvar id is 384683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-84858449-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.852 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPK3	NM_020778.5	c.3711C>T	p.Asp1237=	synonymous_variant	6/14	ENST00000258888.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPK3	ENST00000258888.6	c.3711C>T	p.Asp1237=	synonymous_variant	6/14	1	NM_020778.5	P1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10184 AN: 151918 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0779

Gnomad SAS AF: 0.0262

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0607

GnomAD3 exomes AF: 0.0606 AC: 10749 AN: 177506 Hom.: 377 AF XY: 0.0584 AC XY: 5573 AN XY: 95392

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.0804

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0605

GnomAD4 exome AF: 0.0646 AC: 91404 AN: 1414962 Hom.: 3056 Cov.: 36 AF XY: 0.0635 AC XY: 44422 AN XY: 699956

Gnomad4 AFR exome AF: 0.0694

Gnomad4 AMR exome AF: 0.0584

Gnomad4 ASJ exome AF: 0.0366

Gnomad4 EAS exome AF: 0.0820

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.0641

Gnomad4 NFE exome AF: 0.0677

Gnomad4 OTH exome AF: 0.0684

GnomAD4 genome AF: 0.0670 AC: 10189 AN: 152036 Hom.: 355 Cov.: 32 AF XY: 0.0642 AC XY: 4772 AN XY: 74310

Gnomad4 AFR AF: 0.0708

Gnomad4 AMR AF: 0.0613

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.0779

Gnomad4 SAS AF: 0.0262

Gnomad4 FIN AF: 0.0619

Gnomad4 NFE AF: 0.0697

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.0662 Hom.: 143

Bravo AF: 0.0687

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2018	p.Asp1439Asp in exon 6 of ALPK3: This variant is not expected to have clinical s ignificance because it has been identified in 10.6% (3091/29048) of total chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35931910). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ALPK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.0
Dann	Benign	0.33

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: rs35931910; hg19: chr15-85401680; COSMIC: COSV51930508;