rs41291161

Variant names:

• chr2-21026968-A-T
• rs41291161
• NM_000384.3:c.2068-4T>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000384.3(APOB):​c.2068-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,142 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: APOB NM_000384.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001199
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 1.07

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-21026968-A-T is Benign according to our data. Variant chr2-21026968-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402372.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=1}. Variant chr2-21026968-A-T is described in Lovd as [Benign]. Variant chr2-21026968-A-T is described in Lovd as [Likely_benign]. Variant chr2-21026968-A-T is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAdExome4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.2068-4T>A		splice_region_variant, intron_variant	Intron 14 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.2068-4T>A		splice_region_variant, intron_variant	Intron 14 of 28	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000399256.4	c.2068-4T>A		splice_region_variant, intron_variant	Intron 14 of 16	1		ENSP00000382200.4
APOB	ENST00000673739.2	n.*1374-4T>A		splice_region_variant, intron_variant	Intron 13 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.*1374-4T>A		splice_region_variant, intron_variant	Intron 13 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00131 AC: 328 AN: 250808 Hom.: 4 AF XY: 0.00142 AC XY: 193 AN XY: 135678

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00127 AC: 1854 AN: 1461794 Hom.: 10 Cov.: 32 AF XY: 0.00130 AC XY: 948 AN XY: 727194

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74494

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00219 Hom.: 1

Bravo AF: 0.00117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOB: BP4, BS2 -

Apr 09, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18492086, 23593297, 17570373, 26332594) -

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not in splice consensus -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B Uncertain:1

Apr 16, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

APOB-related disorder Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APOB c.2068-4T>A variant is predicted to interfere with splicing. The c.2068-4T>A substitution is not predicted to alter mRNA splicing (Alamut Visual plus v1.6.1). However it was reported in the compound heterozygous state in two unrelated patients with familial hypobetalipoproteinemia (FHBL) who also harbored a second protein truncating variant in the APOB gene (Tarugi et al. 2007. PubMed ID: 17570373; Di Leo et al. 2008. PubMed ID: 18492086). Di Leo et al. also showed that in vitro the c.2068-4T>A substitution did not alter normal mRNA splicing. FHBL is inherited in a co-dominant manner and is almost always associated with protein truncating variants in the APOB gene (Tarugi et al. 2007. PubMed ID: 17570373). FHBL heterozygotes may be asymptomatic or display symptoms of FHBL to varying degrees. This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:1

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 06, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Familial hypercholesterolemia Benign:1

Jun 28, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.3
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0060
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: rs41291161; hg19: chr2-21249840;