rs55752937

Positions:

chr15-84858366-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020778.5(ALPK3):c.3628C>T(p.Arg1210Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,554,078 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 92 hom., cov: 32)

Exomes 𝑓: 0.011 ( 137 hom. )

Consequence

ALPK3
NM_020778.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0790

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026003122).

BP6

Variant 15-84858366-C-T is Benign according to our data. Variant chr15-84858366-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 383786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-84858366-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPK3	NM_020778.5 linkuse as main transcript	c.3628C>T	p.Arg1210Trp	missense_variant	6/14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6 linkuse as main transcript	c.3628C>T	p.Arg1210Trp	missense_variant	6/14	1	NM_020778.5	ENSP00000258888	P1

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

3376

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0546

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.0259

GnomAD3 exomes

AF:

0.0117

AC:

1838

AN:

157146

Hom.:

AF XY:

0.0107

AC XY:

893

AN XY:

83804

show subpopulations

Gnomad AFR exome

AF:

0.0550

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00980

Gnomad SAS exome

AF:

0.00388

Gnomad FIN exome

AF:

0.000857

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0115

AC:

16097

AN:

1401888

Hom.:

137

Cov.:

AF XY:

0.0110

AC XY:

7602

AN XY:

692226

show subpopulations

Gnomad4 AFR exome

AF:

0.0543

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.0130

Gnomad4 SAS exome

AF:

0.00336

Gnomad4 FIN exome

AF:

0.000705

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0223

AC:

3387

AN:

152190

Hom.:

Cov.:

AF XY:

0.0209

AC XY:

1555

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0547

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.0101

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.0256

Alfa

AF:

0.0125

Hom.:

Bravo

AF:

0.0253

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.0480

AC:

205

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.00753

AC:

855

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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 23, 2018	p.Arg1412Trp in exon 6 of ALPK3: This variant is not expected to have clinical s ignificance because it has been identified in 7.4% (153/2070) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55752937). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardiomyopathy, familial hypertrophic 27

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.23

MPC

0.14

ClinPred

0.029

GERP RS

0.23

Varity_R

0.22

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over