chr2-21041028-G-A

Position:

• chr2-21041028-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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:17 O:1
• Conservation: PhyloP100: 3.67

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]

ACMG classification

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/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.293C>T	p.Thr98Ile	missense_variant	4/29	ENST00000233242.5	NP_000375.3

Ensembl

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

GnomAD3 exomes AF: 0.258 AC: 64618 AN: 250438 Hom.: 9147 AF XY: 0.257 AC XY: 34729 AN XY: 135304

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

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.: 33 AF XY: 0.239 AC XY: 17745 AN XY: 74350

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:1 Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2016	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

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2017	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Familial hypobetalipoproteinemia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Jun 06, 2022	ACMG Guidelines, 2015; BA1-Allele frequency is >5% in GnomAD_exome -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

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

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

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
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

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

Other links and lift over

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