rs12713844

Positions:

chr2-21015541-C-G

Variant summary

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

The NM_000384.3(APOB):c.3337G>C(p.Asp1113His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,612,412 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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 same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0073 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 96 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:16

Conservation

PhyloP100: 0.911

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=0.0044953525).

BP6

Variant 2-21015541-C-G is Benign according to our data. Variant chr2-21015541-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218443.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=9}. Variant chr2-21015541-C-G is described in Lovd as [Benign]. Variant chr2-21015541-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.3337G>C	p.Asp1113His	missense_variant	22/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
APOB	ENST00000233242.5 linkuse as main transcript	c.3337G>C	p.Asp1113His	missense_variant	22/29	1	NM_000384.3	P1
APOB	ENST00000673739.2 linkuse as main transcript	c.*2643G>C		3_prime_UTR_variant, NMD_transcript_variant	21/25
APOB	ENST00000673882.2 linkuse as main transcript	c.*2432G>C		3_prime_UTR_variant, NMD_transcript_variant	20/23

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1113

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00767

GnomAD3 exomes

AF:

0.00674

AC:

1681

AN:

249556

Hom.:

AF XY:

0.00678

AC XY:

915

AN XY:

134960

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00356

Gnomad FIN exome

AF:

0.00349

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00849

GnomAD4 exome

AF:

0.00847

AC:

12369

AN:

1460252

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

6011

AN XY:

726436

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.0102

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00363

Gnomad4 FIN exome

AF:

0.00490

Gnomad4 NFE exome

AF:

0.00975

Gnomad4 OTH exome

AF:

0.00676

GnomAD4 genome

AF:

0.00731

AC:

1113

AN:

152160

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

522

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00759

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00699

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00682

AC:

828

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0107

EpiControl

AF:

0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Pathogenic:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2017	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. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia, familial, 1

Uncertain:1Benign:4

Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	1Hmz + 1Htz/88 non-FH individuals -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	APOB: BP4, BS2 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2016

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

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.054

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.65

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.10

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0080

Vest4

0.27

MVP

0.63

MPC

0.29

ClinPred

0.026

GERP RS

3.6

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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