rs17240441

chr2-21043902-GGCAGCGCCA-Gchr2-21043902-GGCAGCGCCA-GGCAGCGCCAGCAGCGCCA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000384.3(APOB):c.35_43del(p.Leu12_Leu14del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,424,858 control chromosomes in the GnomAD database, including 69,415 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5880 hom., cov: 20)
  • Exomes 𝑓: 0.31 (63535 hom.)
• Consequence: APOB NM_000384.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 2.29

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 -16 ACMG points.

• BP6: Variant 2-21043902-GGCAGCGCCA-G is Benign according to our data. Variant chr2-21043902-GGCAGCGCCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 255983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21043902-GGCAGCGCCA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.35_43del	p.Leu12_Leu14del	inframe_deletion	1/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.35_43del	p.Leu12_Leu14del	inframe_deletion	1/29	1	NM_000384.3	P1
APOB	ENST00000399256.4	c.35_43del	p.Leu12_Leu14del	inframe_deletion	1/17	1
APOB	ENST00000673739.2	c.35_43del	p.Leu12_Leu14del	inframe_deletion, NMD_transcript_variant	1/25
APOB	ENST00000673882.2	c.35_43del	p.Leu12_Leu14del	inframe_deletion, NMD_transcript_variant	1/23

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41523 AN: 151310 Hom.: 5870 Cov.: 20

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.252

GnomAD3 exomes AF: 0.122 AC: 6596 AN: 54138 Hom.: 819 AF XY: 0.122 AC XY: 3927 AN XY: 32120

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0843

Gnomad EAS exome AF: 0.0486

Gnomad SAS exome AF: 0.0706

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.307 AC: 390913 AN: 1273442 Hom.: 63535 AF XY: 0.302 AC XY: 189368 AN XY: 626708

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.275 AC: 41577 AN: 151416 Hom.: 5880 Cov.: 20 AF XY: 0.271 AC XY: 20029 AN XY: 74010

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.255

Alfa AF: 0.111 Hom.: 175

Bravo AF: 0.280

Asia WGS AF: 0.184 AC: 634 AN: 3440

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:13

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, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia, familial, 1 Benign:3

Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
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: 26.862% in gnomAD_Genomes) 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.In-frame deletion in a repetitive region is less likely to be pathogenic. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

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. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Cohesion Phenomics

Sep 19, 2022

- -

APOB POLYMORPHISM IN SIGNAL PEPTIDE Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Mar 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17240441; hg19: chr2-21266774;