rs754264874

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000384.3(APOB):c.10519C>T(p.Arg3507Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3507P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 0.197

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-21006348-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.10519C>T	p.Arg3507Trp	missense_variant	26/29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.10519C>T	p.Arg3507Trp	missense_variant	26/29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250624

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000766

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 26, 2019

The c.10519C>T (p.Arg3507Trp) variant in the APOB gene has been reported in an individual with mild to moderate hypercholesterolemia (PMID: 11115503) and in Dutch patients with FH (PMID: 16250003). Also known as p.Arg3480Trp, functional studies showed that this variant reduced the binding of LDL to the LDL receptor (PMID: 11115503). This variant is observed at a frequency of 6/282024 in the gnomAD population database. A different missense change at the same amino acid, p.Arg3507Pro, has also been reported in individuals with hypercholesterolemia (PMID: 7882518, 16250003). In light of the currently available data this c.10519C>T (p.Arg3507Trp) variant is classified as likely pathogenic. -

Hypercholesterolemia, familial, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation;literature only

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The p.R3507W variant (also known as c.10519C>T), located in coding exon 26 of the APOB gene, results from a C to T substitution at nucleotide position 10519. The arginine at codon 3507 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as p.R3480W) has been detected in individuals with hypercholesterolemia or premature coronary artery disease; however, this variant has also been detected in an individual reported to have features of hypobetalipoproteinemia (Borén J et al. J Biol Chem, 2001 Mar;276:9214-8; Benn M et al. J Biol Chem, 2005 Jun;280:21052-60; Murdock DR et al. Genet Med, 2021 Dec;23:2404-2414). Functional studies suggest this variant may alter protein function; however, additional evidence is needed to confirm this finding (Borén J et al. J Biol Chem, 2001 Mar;276:9214-8; Benn M et al. J Biol Chem, 2005 Jun;280:21052-60). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.0086

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.44

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.71

PrimateAI

Benign

0.18

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.49

Sift

Benign

0.11

Sift4G

Benign

0.17

Vest4

0.44

MVP

0.84

MPC

0.044

ClinPred

0.069

GERP RS

3.9

gMVP

0.55

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