rs72653095

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000384.3(APOB):c.8462C>T(p.Pro2821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,940 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. P2821P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 14 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 1.79

Publications

21 publications found

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 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

APOB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077530444).

BP6

Variant 2-21008406-G-A is Benign according to our data. Variant chr2-21008406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218451.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=2, Benign=5, Likely_benign=7}.

BS2

High Homozygotes in GnomAdExome4 at 14 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.8462C>T	p.Pro2821Leu	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.8462C>T	p.Pro2821Leu	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

453

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00420

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00114

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00406

AC:

1021

AN:

251208

AF XY:

0.00449

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00983

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.00424

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00399

AC:

5831

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

3010

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33472

American (AMR)

AF:

0.00246

AC:

110

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00838

AC:

219

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00834

AC:

719

AN:

86254

European-Finnish (FIN)

AF:

0.00217

AC:

116

AN:

53412

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00393

AC:

4367

AN:

1111948

Other (OTH)

AF:

0.00402

AC:

243

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

382

764

1146

1528

1910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00298

AC:

454

AN:

152146

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

41514

American (AMR)

AF:

0.00419

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0112

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00385

AC:

262

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00377

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 09, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely 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 -

Apr 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22995991, 24503134, 20657596, 18710658, 19602640, 27884173, 27153395, 30526649) -

not specified

Benign:3

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

BS1;BP4 -

PreventionGenetics, part of Exact Sciences

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: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: High frequency -

Hypercholesterolemia, familial, 1

Uncertain:1Benign:1

Feb 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

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

- -

Familial hypobetalipoproteinemia 1

Uncertain:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

May 14, 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. -

Familial hypercholesterolemia

Benign:1

Nov 28, 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

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.41

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.83

PhyloP100

1.8

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.097

Sift

Benign

0.051

Sift4G

Uncertain

0.014

Vest4

0.27

MVP

0.67

MPC

0.28

ClinPred

0.019

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.67

Mutation Taster

=95/5

polymorphism

(source)

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

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rs72653095

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over