2-21003040-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000384.3(APOB):c.12382G>A(p.Val4128Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,567,456 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 56 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: -1.85

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028062165).

BP6

Variant 2-21003040-C-T is Benign according to our data. Variant chr2-21003040-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384812.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=2}. Variant chr2-21003040-C-T is described in Lovd as [Benign]. Variant chr2-21003040-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.12382G>A	p.Val4128Met	missense_variant	Exon 29 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.12382G>A	p.Val4128Met	missense_variant	Exon 29 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.00558

AC:

849

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00459

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00931

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00588

AC:

1275

AN:

217010

Hom.:

AF XY:

0.00627

AC XY:

727

AN XY:

115930

show subpopulations

Gnomad AFR exome

AF:

0.000949

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.000888

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00446

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.00866

Gnomad OTH exome

AF:

0.00957

GnomAD4 exome

AF:

0.00722

AC:

10220

AN:

1415200

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

5024

AN XY:

698580

show subpopulations

Gnomad4 AFR exome

AF:

0.00166

Gnomad4 AMR exome

AF:

0.00426

Gnomad4 ASJ exome

AF:

0.000691

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.00525

Gnomad4 FIN exome

AF:

0.00539

Gnomad4 NFE exome

AF:

0.00809

Gnomad4 OTH exome

AF:

0.00747

GnomAD4 genome

AF:

0.00558

AC:

849

AN:

152256

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00481

Gnomad4 NFE

AF:

0.00931

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00794

Hom.:

Bravo

AF:

0.00501

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00605

AC:

734

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOB: BP4, BS2 -

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Nov 21, 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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial hypercholesterolemia

Benign:2

Jul 14, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 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

May 11, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype

Benign:1

Jan 12, 2016

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

0.083

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.054

DANN

Benign

0.57

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.040

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.18

PROVEAN

Benign

0.16

REVEL

Benign

0.024

Sift

Benign

0.62

Sift4G

Benign

0.68

Vest4

0.065

MVP

0.15

MPC

0.037

ClinPred

0.0019

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.099

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