rs12713450

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000384.3(APOB):c.13451C>T(p.Thr4484Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,613,886 control chromosomes in the GnomAD database, including 522 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T4484T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.034 ( 221 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 301 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:15

Conservation

PhyloP100: 2.31

Publications

12 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017679632).

BP6

Variant 2-21001971-G-A is Benign according to our data. Variant chr2-21001971-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255978.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.13451C>T	p.Thr4484Met	missense	Exon 29 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.13451C>T	p.Thr4484Met	missense	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5124

AN:

152058

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.00304

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0114

AC:

2860

AN:

250286

AF XY:

0.00945

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00605

AC:

8850

AN:

1461710

Hom.:

301

Cov.:

AF XY:

0.00574

AC XY:

4176

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.117

AC:

3911

AN:

33470

American (AMR)

AF:

0.0127

AC:

567

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

249

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39684

South Asian (SAS)

AF:

0.00153

AC:

132

AN:

86252

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.0619

AC:

357

AN:

5766

European-Non Finnish (NFE)

AF:

0.00254

AC:

2820

AN:

1111950

Other (OTH)

AF:

0.0133

AC:

804

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

528

1056

1584

2112

2640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.0337

AC:

5135

AN:

152176

Hom.:

221

Cov.:

AF XY:

0.0324

AC XY:

2407

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.107

AC:

4444

AN:

41498

American (AMR)

AF:

0.0217

AC:

332

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00304

AC:

207

AN:

68004

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

236

472

709

945

1181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0156

Hom.:

225

Bravo

AF:

0.0393

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.101

AC:

444

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.0129

AC:

1563

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00510

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hypercholesterolemia, familial, 1 (3)

Familial hypercholesterolemia (2)

Familial hypobetalipoproteinemia 1 (2)

not provided (2)

Cardiovascular phenotype (1)

Hypercholesterolemia, autosomal dominant, type B (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.5

(source)

DANN

Benign

0.54

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.30

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

PhyloP100

2.3

PrimateAI

Benign

0.26

PROVEAN

Benign

1.5

REVEL

Benign

0.033

Sift

Benign

0.86

Sift4G

Benign

0.34

Vest4

0.018

MPC

0.038

ClinPred

0.0059

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.15

Mutation Taster

=95/5

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