rs12691202

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000384.3(APOB):c.2188G>A(p.Val730Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,613,814 control chromosomes in the GnomAD database, including 980 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.027 ( 55 hom., cov: 32)

Exomes 𝑓: 0.033 ( 925 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 1.04

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005947888).

BP6

Variant 2-21026844-C-T is Benign according to our data. Variant chr2-21026844-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128421.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Likely_benign=2, Uncertain_significance=3}. Variant chr2-21026844-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0267 (4071/152286) while in subpopulation AMR AF= 0.0354 (542/15296). AF 95% confidence interval is 0.0342. There are 55 homozygotes in gnomad4. There are 2013 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 55 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.2188G>A	p.Val730Ile	missense_variant	15/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
APOB	ENST00000233242.5 linkuse as main transcript	c.2188G>A	p.Val730Ile	missense_variant	15/29	1	NM_000384.3	P1
APOB	ENST00000399256.4 linkuse as main transcript	c.2188G>A	p.Val730Ile	missense_variant	15/17	1
APOB	ENST00000673739.2 linkuse as main transcript	c.*1494G>A		3_prime_UTR_variant, NMD_transcript_variant	14/25
APOB	ENST00000673882.2 linkuse as main transcript	c.*1494G>A		3_prime_UTR_variant, NMD_transcript_variant	14/23

Frequencies

GnomAD3 genomes

AF:

0.0268

AC:

4072

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00656

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0355

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0520

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0354

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0271

AC:

6818

AN:

251322

Hom.:

117

AF XY:

0.0268

AC XY:

3636

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00591

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0511

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00389

Gnomad FIN exome

AF:

0.0480

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0326

GnomAD4 exome

AF:

0.0335

AC:

48895

AN:

1461528

Hom.:

925

Cov.:

AF XY:

0.0326

AC XY:

23676

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00508

Gnomad4 AMR exome

AF:

0.0247

Gnomad4 ASJ exome

AF:

0.0489

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00398

Gnomad4 FIN exome

AF:

0.0450

Gnomad4 NFE exome

AF:

0.0375

Gnomad4 OTH exome

AF:

0.0310

GnomAD4 genome

AF:

0.0267

AC:

4071

AN:

152286

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

2013

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00654

Gnomad4 AMR

AF:

0.0354

Gnomad4 ASJ

AF:

0.0568

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0520

Gnomad4 NFE

AF:

0.0354

Gnomad4 OTH

AF:

0.0350

Alfa

AF:

0.0340

Hom.:

Bravo

AF:

0.0251

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0351

AC:

302

ExAC

AF:

0.0250

AC:

3035

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0348

EpiControl

AF:

0.0375

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2017	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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, flagged submission	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2014	- -

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Uncertain significance, flagged submission	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Familial hypercholesterolemia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 3.501%% (rs12691202, 4518/129062 alleles, 74 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 11, 2022	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 19, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypobetalipoproteinemia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2016

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

-0.65

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.13

Sift

Benign

0.16

T;T

Sift4G

Pathogenic

0.0

D;D

Vest4

0.15

MPC

0.042

ClinPred

0.011

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.76

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