rs12713450

Variant names:

• chr2-21001971-G-A
• rs12713450
• NM_000384.3:c.13451C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21001971-G-A
• chr2-21001971-G-C
• chr2-21001971-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000384.3(APOB):​c.13451C>T​(p.Thr4484Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,613,886 control chromosomes in the GnomAD database, including 522 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. T4484T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (221 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (301 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: 2.31
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017679632).
• BP6: Variant 2-21001971-G-A is Benign according to our data. Variant chr2-21001971-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255978.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.13451C>T	p.Thr4484Met	missense	Exon 29 of 29	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.13451C>T	p.Thr4484Met	missense	Exon 29 of 29	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5124 AN: 152058 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0114 AC: 2860 AN: 250286 AF XY: 0.00945

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00605 AC: 8850 AN: 1461710 Hom.: 301 Cov.: 32 AF XY: 0.00574 AC XY: 4176 AN XY: 727160

African (AFR) AF: 0.117 AC: 3911 AN: 33470

American (AMR) AF: 0.0127 AC: 567 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 249 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86252

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53346

Middle Eastern (MID) AF: 0.0619 AC: 357 AN: 5766

European-Non Finnish (NFE) AF: 0.00254 AC: 2820 AN: 1111950

Other (OTH) AF: 0.0133 AC: 804 AN: 60390

GnomAD4 genome AF: 0.0337 AC: 5135 AN: 152176 Hom.: 221 Cov.: 32 AF XY: 0.0324 AC XY: 2407 AN XY: 74398

African (AFR) AF: 0.107 AC: 4444 AN: 41498

American (AMR) AF: 0.0217 AC: 332 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.00304 AC: 207 AN: 68004

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0156 Hom.: 225

Bravo AF: 0.0393

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.101 AC: 444

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.0129 AC: 1563

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Jan 09, 2017

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.

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 13, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypercholesterolemia, familial, 1 Uncertain:2 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

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

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

not provided Benign:2

Jan 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hypobetalipoproteinemia 1 Benign:2

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.

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hypercholesterolemia Benign:2

Feb 09, 2023

Cohesion Phenomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 17, 2022

GENinCode PLC

Significance: Benign

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

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.

Cardiovascular phenotype Benign:1

Feb 26, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.5
DANN	Benign	0.54
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.30	N
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.99	T
PhyloP100		2.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.033
Sift	Benign	0.86	T
Sift4G	Benign	0.34	T
Vest4		0.018
MPC		0.038
ClinPred		0.0059	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.15
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12713450; hg19: chr2-21224843; COSMIC: COSV51941523; COSMIC: COSV51941523;