rs1367117

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.293C>T(p.Thr98Ile) variant causes a missense change. The variant allele was found at a frequency of 0.296 in 1,612,808 control chromosomes in the GnomAD database, including 75,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.24 ( 5072 hom., cov: 33)

Exomes 𝑓: 0.30 ( 70081 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:17O:1

Conservation

PhyloP100: 3.67

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012553781).

BP6

Variant 2-21041028-G-A is Benign according to our data. Variant chr2-21041028-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21041028-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.293C>T	p.Thr98Ile	missense_variant	Exon 4 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOB	ENST00000233242.5 link	c.293C>T	p.Thr98Ile	missense_variant	Exon 4 of 29	1	NM_000384.3	ENSP00000233242.1	P04114
APOB	ENST00000399256.4 link	c.293C>T	p.Thr98Ile	missense_variant	Exon 4 of 17	1		ENSP00000382200.4	A8MUN2
APOB	ENST00000673739.2 link	n.293C>T		non_coding_transcript_exon_variant	Exon 4 of 25			ENSP00000501110.2	A0A669KB70
APOB	ENST00000673882.2 link	n.293C>T		non_coding_transcript_exon_variant	Exon 4 of 23			ENSP00000501253.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36763

AN:

152006

Hom.:

5068

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.300

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.274

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.221

GnomAD3 exomes

AF:

0.258

AC:

64618

AN:

250438

Hom.:

9147

AF XY:

0.257

AC XY:

34729

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.290

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.126

Gnomad SAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.273

Gnomad NFE exome

AF:

0.320

Gnomad OTH exome

AF:

0.273

GnomAD4 exome

AF:

0.301

AC:

440214

AN:

1460684

Hom.:

70081

Cov.:

AF XY:

0.297

AC XY:

215892

AN XY:

726626

show subpopulations

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.103

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.279

Gnomad4 NFE exome

AF:

0.332

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.242

AC:

36782

AN:

152124

Hom.:

5072

Cov.:

AF XY:

0.239

AC XY:

17745

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.117

Gnomad4 AMR

AF:

0.300

Gnomad4 ASJ

AF:

0.183

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.274

Gnomad4 NFE

AF:

0.318

Gnomad4 OTH

AF:

0.221

Alfa

AF:

0.286

Hom.:

13981

Bravo

AF:

0.240

TwinsUK

AF:

0.337

AC:

1250

ALSPAC

AF:

0.330

AC:

1271

ESP6500AA

AF:

0.127

AC:

559

ESP6500EA

AF:

0.314

AC:

2699

ExAC

AF:

0.257

AC:

31226

Asia WGS

AF:

0.145

AC:

504

AN:

3478

EpiCase

AF:

0.308

EpiControl

AF:

0.311

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:3

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 33.711% 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypobetalipoproteinemia 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia

Benign:2

Jun 23, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2022

Cohesion Phenomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Guidelines, 2015; BA1-Allele frequency is >5% in GnomAD_exome -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 10, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Warfarin response

Other:1

Aug 31, 2010

Pharmacogenomics Lab, Chungbuk National University

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

In patients receiving warfarin after mechanical valve replacement, A allele carriers of rs1367117 had 8.6 times increased risk of bleeding. likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

.;T

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.010

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.56

.;T

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

N;D

REVEL

Benign

0.093

Sift

Benign

0.073

T;T

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.15

MPC

0.039

ClinPred

0.019

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.48

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