2-21006128-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000384.3(APOB):c.10740C>G(p.Asn3580Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N3580N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 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: -0.931

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010568529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.10740C>G	p.Asn3580Lys	missense_variant	Exon 26 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.10740C>G	p.Asn3580Lys	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

250932

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00000562

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000576

AC:

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;C4551990:Familial hypobetalipoproteinemia 1

Uncertain:1Benign:1

Dec 17, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10740C>G (p.Asn3580Lys) variant identified in the APOB gene substitutes an Asparagine for Lysine at amino acid 3580/4564 (exon 26/29).This amino acid is not very well conserved outside of larger mammalian species, and there is an endogenous Lysine at this position in some smaller mammalian species (Vole, Hamster). This variant is found with low frequency in gnomAD(v3.1.2)(13 heterozygotes, 0 homozygotes; allele frequency: 8.55e-5), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.997) and Benign (REVEL; score:0.037) to the function of the canonical transcript. This variant is reported in ClinVar as Pathogenic, Likely Benign, and Benign (VarID:440517), and has been reported in 2 affected individuals in the literature [PMID:31153847, 29572815] as well as once in an individual from a healthy cohort with unclear clinical significance [PMID:32719484]. Given the lack of compelling evidence for its pathogenicity, the c.10740C>G (p.Asn3580Lys) variant identified in the APOB gene is reported as a Variant of Uncertain Significance. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1

Pathogenic:1

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Uncertain:1

Mar 23, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 29572815, 31153847) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

DANN

Benign

0.58

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.12

M_CAP

Benign

0.017

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.80

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

0.96

Vest4

0.029

MutPred

0.35

Gain of ubiquitination at N3580 (P = 0.0155);

MVP

0.42

MPC

0.040

ClinPred

0.030

GERP RS

-7.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.26

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