rs12714214

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000384.3(APOB):c.1661C>T(p.Pro554Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000497 in 1,613,704 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P554R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 6.82

Publications

16 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016731203).

BP6

Variant 2-21028495-G-A is Benign according to our data. Variant chr2-21028495-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199684.

BS2

High Homozygotes in GnomAd4 at 4 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.1661C>T	p.Pro554Leu	missense	Exon 13 of 29	NP_000375.3	P04114

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOB	ENST00000233242.5	TSL:1 MANE Select	c.1661C>T	p.Pro554Leu	missense	Exon 13 of 29	ENSP00000233242.1	P04114
APOB	ENST00000399256.4	TSL:1	c.1661C>T	p.Pro554Leu	missense	Exon 13 of 17	ENSP00000382200.4	A8MUN2
APOB	ENST00000673739.2		n.*967C>T		non_coding_transcript_exon	Exon 12 of 25	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00898

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000681

AC:

171

AN:

251160

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.00861

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000276

AC:

404

AN:

1461448

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.00774

AC:

259

AN:

33474

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000764

AC:

AN:

1111936

Other (OTH)

AF:

0.000464

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00261

AC:

398

AN:

152256

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00895

AC:

372

AN:

41562

American (AMR)

AF:

0.00131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000867

Hom.:

Bravo

AF:

0.00283

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000898

AC:

109

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Familial hypobetalipoproteinemia 1 (1)

Hypercholesterolemia, autosomal dominant, type B (1)

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

Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.054

PhyloP100

6.8

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Vest4

0.66

MVP

0.91

MPC

0.28

ClinPred

0.11

GERP RS

5.7

gMVP

0.40

Mutation Taster

=77/23

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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