rs17240441

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000384.3(APOB):c.35_43delTGGCGCTGC(p.Leu12_Leu14del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14

Conservation

PhyloP100: 2.29

Publications

33 publications found

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 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

APOB links:

ENSG00000299295 (HGNC:):

ENSG00000299295 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 255983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.35_43delTGGCGCTGC	p.Leu12_Leu14del	disruptive_inframe_deletion	Exon 1 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.35_43delTGGCGCTGC	p.Leu12_Leu14del	disruptive_inframe_deletion	Exon 1 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41523

AN:

151310

Hom.:

5870

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.122

AC:

6596

AN:

54138

AF XY:

0.122

show subpopulations

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 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

show subpopulations

African (AFR)

AF:

0.187

AC:

4751

AN:

25350

American (AMR)

AF:

0.297

AC:

6239

AN:

21042

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

4175

AN:

21176

East Asian (EAS)

AF:

0.190

AC:

5203

AN:

27422

South Asian (SAS)

AF:

0.149

AC:

9959

AN:

66768

European-Finnish (FIN)

AF:

0.273

AC:

8605

AN:

31512

Middle Eastern (MID)

AF:

0.201

AC:

762

AN:

3790

European-Non Finnish (NFE)

AF:

0.329

AC:

336725

AN:

1024254

Other (OTH)

AF:

0.278

AC:

14494

AN:

52128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11528

23057

34585

46114

57642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11434

22868

34302

45736

57170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.275

AC:

41577

AN:

151416

Hom.:

5880

Cov.:

AF XY:

0.271

AC XY:

20029

AN XY:

74010

show subpopulations

African (AFR)

AF:

0.209

AC:

8643

AN:

41414

American (AMR)

AF:

0.328

AC:

4977

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

744

AN:

3470

East Asian (EAS)

AF:

0.202

AC:

1036

AN:

5134

South Asian (SAS)

AF:

0.151

AC:

731

AN:

4826

European-Finnish (FIN)

AF:

0.274

AC:

2863

AN:

10430

Middle Eastern (MID)

AF:

0.186

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.321

AC:

21699

AN:

67650

Other (OTH)

AF:

0.255

AC:

536

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1470

2940

4410

5880

7350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

Nov 22, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Hypercholesterolemia, familial, 1

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1Benign:1

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 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. -

Familial hypercholesterolemia

Benign:2

Sep 19, 2022

Cohesion Phenomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

APOB POLYMORPHISM IN SIGNAL PEPTIDE

Benign:1

Mar 01, 1990

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=186/14

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over