rs533617

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000384.3(APOB):c.5768A>G(p.His1923Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,614,200 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1923Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 93 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1168 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 8.02

Publications

49 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial hypobetalipoproteinemia 1
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APOB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038963258).

BP6

Variant 2-21011100-T-C is Benign according to our data. Variant chr2-21011100-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0286 (4353/152346) while in subpopulation NFE AF = 0.041 (2791/68030). AF 95% confidence interval is 0.0398. There are 93 homozygotes in GnomAd4. There are 2232 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 93 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.5768A>G	p.His1923Arg	missense	Exon 26 of 29	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.5768A>G	p.His1923Arg	missense	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4352

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00750

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0403

Gnomad FIN

AF:

0.0661

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0410

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0314

AC:

7901

AN:

251320

AF XY:

0.0320

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.00917

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0675

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0366

AC:

53503

AN:

1461854

Hom.:

1168

Cov.:

AF XY:

0.0367

AC XY:

26707

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00502

AC:

168

AN:

33476

American (AMR)

AF:

0.00995

AC:

445

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

679

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0370

AC:

3188

AN:

86254

European-Finnish (FIN)

AF:

0.0661

AC:

3529

AN:

53420

Middle Eastern (MID)

AF:

0.0352

AC:

203

AN:

5768

European-Non Finnish (NFE)

AF:

0.0390

AC:

43383

AN:

1111984

Other (OTH)

AF:

0.0315

AC:

1905

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3251

6502

9752

13003

16254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1608

3216

4824

6432

8040

<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:

0.0286

AC:

4353

AN:

152346

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2232

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00748

AC:

311

AN:

41580

American (AMR)

AF:

0.0116

AC:

178

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4830

European-Finnish (FIN)

AF:

0.0661

AC:

702

AN:

10618

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0410

AC:

2791

AN:

68030

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

221

442

664

885

1106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0343

Hom.:

453

Bravo

AF:

0.0232

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0464

AC:

179

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0376

AC:

323

ExAC

AF:

0.0312

AC:

3783

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0387

EpiControl

AF:

0.0355

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Hypercholesterolemia, familial, 1 (3)

Familial hypercholesterolemia (2)

Cardiovascular phenotype (1)

Hypercholesterolemia, autosomal dominant, type B (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.98

PhyloP100

8.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Vest4

0.52

MPC

0.29

ClinPred

0.016

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.80

Mutation Taster

=27/73

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over