NM_000384.3:c.8216C>T

Variant names:

Variant summary

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

The NM_000384.3(APOB):c.8216C>T(p.Pro2739Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,762 control chromosomes in the GnomAD database, including 57,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.23 ( 5077 hom., cov: 32)

Exomes 𝑓: 0.24 ( 52727 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:16

Conservation

PhyloP100: 10.0

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.93353E-5).

BP6

Variant 2-21008652-G-A is Benign according to our data. Variant chr2-21008652-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21008652-G-A is described in Lovd as [Benign]. Variant chr2-21008652-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.8216C>T	p.Pro2739Leu	missense_variant	Exon 26 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.8216C>T	p.Pro2739Leu	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34945

AN:

151902

Hom.:

5077

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.732

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.228

GnomAD3 exomes

AF:

0.293

AC:

73564

AN:

250888

Hom.:

14050

AF XY:

0.301

AC XY:

40807

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.725

Gnomad SAS exome

AF:

0.503

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.243

AC:

355716

AN:

1461742

Hom.:

52727

Cov.:

AF XY:

0.251

AC XY:

182548

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.255

Gnomad4 ASJ exome

AF:

0.193

Gnomad4 EAS exome

AF:

0.731

Gnomad4 SAS exome

AF:

0.495

Gnomad4 FIN exome

AF:

0.266

Gnomad4 NFE exome

AF:

0.208

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.230

AC:

34947

AN:

152020

Hom.:

5077

Cov.:

AF XY:

0.239

AC XY:

17756

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.227

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.732

Gnomad4 SAS

AF:

0.526

Gnomad4 FIN

AF:

0.262

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.233

Alfa

AF:

0.228

Hom.:

11630

Bravo

AF:

0.221

TwinsUK

AF:

0.207

AC:

767

ALSPAC

AF:

0.204

AC:

787

ESP6500AA

AF:

0.158

AC:

694

ESP6500EA

AF:

0.217

AC:

1862

ExAC

AF:

0.293

AC:

35538

Asia WGS

AF:

0.595

AC:

2066

AN:

3478

EpiCase

AF:

0.225

EpiControl

AF:

0.216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:3

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial hypercholesterolemia

Benign:3

Jun 21, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 25, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated systolic hypertension;C4021419:Triangular shaped proximal phalanx of the thumb;C5139433:Neutrophilia in presence of infection

Pathogenic:1

Phenosystems SA

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hypobetalipoproteinemia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Benign:1

Dec 08, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.25

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.000029

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.72

MPC

0.27

ClinPred

0.037

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.92

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

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