rs17247291

chr2-21005955-C-Tchr2-21005955-C-A

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.10913G>A(p.Arg3638Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 1,613,688 control chromosomes in the GnomAD database, including 6,499 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3638W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.066 (458 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6041 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 3.08

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=0.0017217398).
• BP6: Variant 2-21005955-C-T is Benign according to our data. Variant chr2-21005955-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21005955-C-T is described in Lovd as [Benign]. Variant chr2-21005955-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.10913G>A	p.Arg3638Gln	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.10913G>A	p.Arg3638Gln	missense_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9961 AN: 152046 Hom.: 456 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.0633

GnomAD3 exomes AF: 0.0700 AC: 17541 AN: 250484 Hom.: 790 AF XY: 0.0686 AC XY: 9290 AN XY: 135374

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.0989

Gnomad ASJ exome AF: 0.0502

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.0924

Gnomad OTH exome AF: 0.0788

GnomAD4 exome AF: 0.0861 AC: 125770 AN: 1461524 Hom.: 6041 Cov.: 37 AF XY: 0.0838 AC XY: 60930 AN XY: 727038

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.0785

Gnomad4 NFE exome AF: 0.0972

Gnomad4 OTH exome AF: 0.0762

GnomAD4 genome AF: 0.0655 AC: 9968 AN: 152164 Hom.: 458 Cov.: 32 AF XY: 0.0635 AC XY: 4723 AN XY: 74390

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0536

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0693

Gnomad4 NFE AF: 0.0920

Gnomad4 OTH AF: 0.0632

Alfa AF: 0.0848 Hom.: 1569

Bravo AF: 0.0670

TwinsUK AF: 0.107 AC: 395

ALSPAC AF: 0.106 AC: 410

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.0898 AC: 772

ExAC AF: 0.0686 AC: 8330

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0943

EpiControl AF: 0.0895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 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. -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 31, 2015	p.Arg3638Gln in exon 26 of APOB: This variant is not expected to have clinical s ignificance because it has been identified in 6.9% (8306/120598) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1801701). -
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	-	- -

Hypercholesterolemia, familial, 1 Benign:2

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2017	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 10.653% in TwinsUk) based on the frequency threshold of 1.253% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 hypobetalipoproteinemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Dec 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	11
Dann	Benign	0.61
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.051
MPC		0.040
ClinPred		0.0068	T
GERP RS		3.2
gMVP		0.20

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: rs1801701; hg19: chr2-21228827; COSMIC: COSV51934384;