rs1042034

chr2-21002409-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.587

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 -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	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	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.: 32

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

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.: 33 AF XY: 0.748 AC XY: 537179 AN XY: 718358

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.: 32 AF XY: 0.760 AC XY: 56528 AN XY: 74364

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:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

Hypercholesterolemia, familial, 1 Benign:3

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	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

Hypercholesterolemia, autosomal dominant, type B Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Familial hypobetalipoproteinemia 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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. -

Familial hypercholesterolemia Benign:1

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Feb 09, 2023

- -

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	T
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	N
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.055
Sift	Benign	1.0	T
Sift4G	Benign	0.97	T
Vest4		0.017
MPC		0.035
ClinPred		0.0051	T
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

Other links and lift over

dbSNP: rs1042034; hg19: chr2-21225281; COSMIC: COSV51928341; COSMIC: COSV51928341;