rs1042034

Positions:

chr2-21002409-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.13013G>A(p.Ser4338Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,598,072 control chromosomes in the GnomAD database, including 468,513 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.77 ( 46113 hom., cov: 32)

Exomes 𝑓: 0.76 ( 422400 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 0.587

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.706678E-7).

BP6

Variant 2-21002409-C-T is Benign according to our data. Variant chr2-21002409-C-T is described in ClinVar as [Benign]. Clinvar id is 128418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21002409-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.13013G>A	p.Ser4338Asn	missense_variant	29/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.13013G>A	p.Ser4338Asn	missense_variant	29/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116943

AN:

152010

Hom.:

46056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.849

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.811

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.783

Gnomad OTH

AF:

0.772

GnomAD3 exomes

AF:

0.705

AC:

170441

AN:

241800

Hom.:

63244

AF XY:

0.698

AC XY:

91340

AN XY:

130882

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.740

Gnomad ASJ exome

AF:

0.803

Gnomad EAS exome

AF:

0.273

Gnomad SAS exome

AF:

0.486

Gnomad FIN exome

AF:

0.737

Gnomad NFE exome

AF:

0.785

Gnomad OTH exome

AF:

0.729

GnomAD4 exome

AF:

0.756

AC:

1092526

AN:

1445944

Hom.:

422400

Cov.:

AF XY:

0.748

AC XY:

537179

AN XY:

718358

show subpopulations

Gnomad4 AFR exome

AF:

0.857

Gnomad4 AMR exome

AF:

0.744

Gnomad4 ASJ exome

AF:

0.806

Gnomad4 EAS exome

AF:

0.266

Gnomad4 SAS exome

AF:

0.494

Gnomad4 FIN exome

AF:

0.734

Gnomad4 NFE exome

AF:

0.792

Gnomad4 OTH exome

AF:

0.738

GnomAD4 genome

AF:

0.769

AC:

117060

AN:

152128

Hom.:

46113

Cov.:

AF XY:

0.760

AC XY:

56528

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.849

Gnomad4 AMR

AF:

0.773

Gnomad4 ASJ

AF:

0.811

Gnomad4 EAS

AF:

0.265

Gnomad4 SAS

AF:

0.463

Gnomad4 FIN

AF:

0.738

Gnomad4 NFE

AF:

0.783

Gnomad4 OTH

AF:

0.767

Alfa

AF:

0.771

Hom.:

78284

Bravo

AF:

0.778

TwinsUK

AF:

0.793

AC:

2940

ALSPAC

AF:

0.796

AC:

3068

ESP6500AA

AF:

0.843

AC:

3708

ESP6500EA

AF:

0.782

AC:

6721

ExAC

AF:

0.703

AC:

85314

Asia WGS

AF:

0.399

AC:

1390

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia, familial, 1

Benign:3

Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 27, 2017	- -

Hypercholesterolemia, autosomal dominant, type B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial hypobetalipoproteinemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial hypercholesterolemia

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 19, 2022	- -

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

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

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. -

Warfarin response

Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.13

DANN

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.015

MetaRNN

Benign

9.7e-7

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

1.2

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

0.97

Vest4

0.017

MPC

0.035

ClinPred

0.0051

GERP RS

1.6

gMVP

0.065

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