chr2-21041028-G-A

Variant names:

• chr2-21041028-G-A
• rs1367117
• NM_000384.3:c.293C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T98T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5072 hom., cov: 33)
  • Exomes 𝑓: 0.30 (70081 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 3.67
• Publications: 251 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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	c.293C>T	p.Thr98Ile	missense_variant	Exon 4 of 29	ENST00000233242.5	NP_000375.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36763 AN: 152006 Hom.: 5068 Cov.: 33

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

GnomAD2 exomes AF: 0.258 AC: 64618 AN: 250438 AF XY: 0.257

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 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.: 35 AF XY: 0.297 AC XY: 215892 AN XY: 726626

African (AFR) AF: 0.101 AC: 3371 AN: 33472

American (AMR) AF: 0.290 AC: 12955 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4894 AN: 26114

East Asian (EAS) AF: 0.103 AC: 4088 AN: 39698

South Asian (SAS) AF: 0.164 AC: 14093 AN: 86100

European-Finnish (FIN) AF: 0.279 AC: 14865 AN: 53306

Middle Eastern (MID) AF: 0.179 AC: 982 AN: 5472

European-Non Finnish (NFE) AF: 0.332 AC: 368595 AN: 1111496

Other (OTH) AF: 0.271 AC: 16371 AN: 60330

GnomAD4 genome AF: 0.242 AC: 36782 AN: 152124 Hom.: 5072 Cov.: 33 AF XY: 0.239 AC XY: 17745 AN XY: 74350

African (AFR) AF: 0.117 AC: 4868 AN: 41514

American (AMR) AF: 0.300 AC: 4591 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 637 AN: 3472

East Asian (EAS) AF: 0.120 AC: 618 AN: 5154

South Asian (SAS) AF: 0.151 AC: 726 AN: 4816

European-Finnish (FIN) AF: 0.274 AC: 2903 AN: 10586

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21625 AN: 67964

Other (OTH) AF: 0.221 AC: 467 AN: 2110

Alfa AF: 0.277 Hom.: 20108

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:1 Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

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

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

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. -

Hypercholesterolemia, familial, 1 Benign:3

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Uncertain:1 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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. -

Hypercholesterolemia, autosomal dominant, type B Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

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 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	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	.;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		3.7
PrimateAI	Benign	0.41	T
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	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.48
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1367117; hg19: chr2-21263900; COSMIC: COSV51928433;