rs12713843

Variant names:

• chr2-21015495-C-T
• rs12713843
• NM_000384.3:c.3383G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000384.3(APOB):​c.3383G>A​(p.Arg1128His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,614,006 control chromosomes in the GnomAD database, including 28 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (25 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13
• Conservation: PhyloP100: 0.144

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007625997).
• BP6: Variant 2-21015495-C-T is Benign according to our data. Variant chr2-21015495-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281142.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=4, Uncertain_significance=5}. Variant chr2-21015495-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.3383G>A	p.Arg1128His	missense_variant	Exon 22 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.3383G>A	p.Arg1128His	missense_variant	Exon 22 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152048 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00769

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00378 AC: 949 AN: 251360 Hom.: 7 AF XY: 0.00412 AC XY: 560 AN XY: 135856

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00463 AC: 6764 AN: 1461840 Hom.: 25 Cov.: 33 AF XY: 0.00464 AC XY: 3373 AN XY: 727218

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.00227

Gnomad4 NFE exome AF: 0.00502

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152166 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74390

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00790

Gnomad4 FIN AF: 0.00208

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00482 Hom.: 8

Bravo AF: 0.00364

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Jun 30, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOB: BP4 -

Jun 01, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14732481, 28008009, 26332594, 21408211, 27153395, 20981092, 30782561, 31150472, 26582918) -

Hypercholesterolemia, autosomal dominant, type B Uncertain:2 Benign:1

Aug 01, 2017

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg1128His variant in APOB has been reported in 2 Caucasian individuals suspected to have familial hypercholesterolemia (DOI: 10.1016/S0735-1097(18)32309-X), and has been identified in 0.7219% (221/30614) of South Asian chromosomes, including 6 homozygotes, 0.4949% (639/129122) of European (non-Finnish) chromosomes, including 3 homozygotes, and 0.3753% (133/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12713843). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 281142). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015). -

Hypercholesterolemia, familial, 1 Benign:3

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: ExAC: 0.7% (116/16506) South Asian chromosomes -

APOB-related disorder Uncertain:1

Feb 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APOB c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. This variant has been reported as a variant of uncertain significance in an individual with primary hypocholesterolemia (Blanco-Vaca et al. 2019. PubMed ID: 30782561). In addition, this variant has been identified in three individuals with low lipid levels (Neale et al. 2011. PubMed ID: 21408211). This variant is reported in 0.72% of alleles in individuals of South Asian descent, and in nine homozygotes in gnomAD (http://gnomad.broadinstitute.org/variant/2-21238367-C-T), which suggests that it may be too common to be a primary cause of disease. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to likely benign, to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/281142/). 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. -

Familial hypobetalipoproteinemia 1 Uncertain:1

Aug 01, 2017

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 18, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial hypercholesterolemia Benign:1

Sep 26, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Pathogenic	1.0
Eigen	Benign	-0.020
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.77	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.096	T
Sift4G	Uncertain	0.0020	D
Vest4		0.37
MVP		0.53
MPC		0.043
ClinPred		0.021	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12713843; hg19: chr2-21238367; COSMIC: COSV51927392;