chr2-21015451-G-A

Position:

chr2-21015451-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000384.3(APOB):c.3427C>T(p.Pro1143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,128 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1143P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 6 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:10

Conservation

PhyloP100: 1.62

Variant links:

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

APOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052723587).

BS2

High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.3427C>T	p.Pro1143Ser	missense_variant	22/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
APOB	ENST00000233242.5 linkuse as main transcript	c.3427C>T	p.Pro1143Ser	missense_variant	22/29	1	NM_000384.3	P1
APOB	ENST00000673739.2 linkuse as main transcript	c.*2733C>T		3_prime_UTR_variant, NMD_transcript_variant	21/25
APOB	ENST00000673882.2 linkuse as main transcript	c.*2522C>T		3_prime_UTR_variant, NMD_transcript_variant	20/23

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

302

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00153

AC:

385

AN:

251442

Hom.:

AF XY:

0.00155

AC XY:

211

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00245

AC:

3580

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

1804

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00293

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152236

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00137

AC:

167

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 04, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	APOB: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	This variant is associated with the following publications: (PMID: 22256951, 18710658) -

Hypercholesterolemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

not specified

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 0.2% European chromosomes -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Aug 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2018	Likely Benign based on current evidence: This variant (also known as p.Pro1116Ser in the mature protein) is a missense variant located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Norwegian individual with hypercholesterolemia (PMID: 18710658) but it has also been identified in 464/277174 chromosomes (0.17%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. -

Hypercholesterolemia, autosomal dominant, type B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

May 10, 2022

ACMG categories: BS2 -

APOB-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The APOB c.3427C>T variant is predicted to result in the amino acid substitution p.Pro1143Ser. This variant has been reported in individuals with hypercholesterolemia or high HDL-C level (Leren et al. 2008. PubMed ID: 18710658; Motazacker et al. 2013. PubMed ID: 23685560. Table SIV). However, it has also been reported in individuals with low lipid or triglyceride levels (Neale et al. 2011. PubMed ID: 21408211; Xing et al. 2012. PubMed ID: 22256951). This variant is reported in 0.28% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In Clinvar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/237744/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2021

This alteration is classified as likely 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

0.074

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.014

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

REVEL

Benign

0.067

Sift

Benign

0.38

Sift4G

Benign

0.43

Vest4

0.12

MVP

0.39

MPC

0.038

ClinPred

0.010

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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