2-21003040-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_000384.3(APOB):c.12382G>A(p.Val4128Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,567,456 control chromosomes in the GnomAD database, including 63 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4128L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 56 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: -1.85

Publications

27 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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-21003040-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3572065.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028062165).

BP6

Variant 2-21003040-C-T is Benign according to our data. Variant chr2-21003040-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 384812.

BS2

High Homozygotes in GnomAd4 at 7 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.12382G>A	p.Val4128Met	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.12382G>A	p.Val4128Met	missense	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.00558

AC:

849

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00459

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00931

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00588

AC:

1275

AN:

217010

AF XY:

0.00627

show subpopulations

Gnomad AFR exome

AF:

0.000949

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.000888

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.00866

Gnomad OTH exome

AF:

0.00957

GnomAD4 exome

AF:

0.00722

AC:

10220

AN:

1415200

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

5024

AN XY:

698580

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

31864

American (AMR)

AF:

0.00426

AC:

165

AN:

38752

Ashkenazi Jewish (ASJ)

AF:

0.000691

AC:

AN:

23162

East Asian (EAS)

AF:

0.0000766

AC:

AN:

39184

South Asian (SAS)

AF:

0.00525

AC:

407

AN:

77586

European-Finnish (FIN)

AF:

0.00539

AC:

279

AN:

51722

Middle Eastern (MID)

AF:

0.00997

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.00809

AC:

8807

AN:

1089188

Other (OTH)

AF:

0.00747

AC:

435

AN:

58224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

562

1125

1687

2250

2812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.00558

AC:

849

AN:

152256

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41548

American (AMR)

AF:

0.00458

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00931

AC:

633

AN:

68014

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

128

170

213

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:

0.00759

Hom.:

Bravo

AF:

0.00501

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00605

AC:

734

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hypercholesterolemia, familial, 1 (3)

not specified (3)

Familial hypercholesterolemia (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

0.083

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.054

(source)

DANN

Benign

0.57

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.040

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

PhyloP100

-1.9

PrimateAI

Benign

0.18

PROVEAN

Benign

0.16

REVEL

Benign

0.024

Sift

Benign

0.62

Sift4G

Benign

0.68

Vest4

0.065

MVP

0.15

MPC

0.037

ClinPred

0.0019

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.099

Mutation Taster

=98/2

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

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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