rs72653066

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000384.3(APOB):c.2604+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,002 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 20 hom., cov: 32)

Exomes 𝑓: 0.011 ( 159 hom. )

Consequence

APOB
NM_000384.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.15

Publications

5 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:

ENSG00000280390 (HGNC:):

ENSG00000280390 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-21023510-C-G is Benign according to our data. Variant chr2-21023510-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 20 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.2604+15G>C		intron_variant	Intron 17 of 28	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOB	ENST00000233242.5 link	c.2604+15G>C	intron_variant	Intron 17 of 28	1	NM_000384.3	ENSP00000233242.1	P04114
ENSG00000280390	ENST00000624225.1 link	n.15C>G	non_coding_transcript_exon_variant	Exon 1 of 1	6
APOB	ENST00000673739.2 link	n.*1910+15G>C	intron_variant	Intron 16 of 24			ENSP00000501110.2	A0A669KB70
APOB	ENST00000673882.2 link	n.*1910+15G>C	intron_variant	Intron 16 of 22			ENSP00000501253.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.00829

AC:

1261

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00899

AC:

2260

AN:

251316

AF XY:

0.00920

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0808

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00347

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0106

AC:

15547

AN:

1461736

Hom.:

159

Cov.:

AF XY:

0.0105

AC XY:

7655

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33478

American (AMR)

AF:

0.00195

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0802

AC:

2096

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00248

AC:

214

AN:

86254

European-Finnish (FIN)

AF:

0.00331

AC:

177

AN:

53404

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0108

AC:

12064

AN:

1111898

Other (OTH)

AF:

0.0134

AC:

807

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

734

1468

2203

2937

3671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.00827

AC:

1260

AN:

152266

Hom.:

Cov.:

AF XY:

0.00735

AC XY:

547

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41552

American (AMR)

AF:

0.00327

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0116

AC:

786

AN:

68014

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0188

Hom.:

Bravo

AF:

0.00822

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2017

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Jun 26, 2018

Illumina Laboratory Services, Illumina

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hypercholesterolemia, familial, 1

Benign:1

Jan 02, 2018

Robarts Research Institute, Western University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypobetalipoproteinemia 1

Benign:1

Jun 26, 2018

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 hypercholesterolemia

Benign:1

Jun 21, 2022

GENinCode PLC

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

-0.84

CADD

Benign

0.40

(source)

DANN

Benign

0.39

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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