2-21002409-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.13013G>A(p.Ser4338Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,598,072 control chromosomes in the GnomAD database, including 468,513 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 Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46113 hom., cov: 32)

Exomes 𝑓: 0.76 ( 422400 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20O:1

Conservation

PhyloP100: 0.587

Publications

160 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=9.706678E-7).

BP6

Variant 2-21002409-C-T is Benign according to our data. Variant chr2-21002409-C-T is described in ClinVar as Benign. ClinVar VariationId is 128418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 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.13013G>A	p.Ser4338Asn	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.13013G>A	p.Ser4338Asn	missense	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116943

AN:

152010

Hom.:

46056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.849

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.772

Gnomad ASJ

AF:

0.811

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.783

Gnomad OTH

AF:

0.772

GnomAD2 exomes

AF:

0.705

AC:

170441

AN:

241800

AF XY:

0.698

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.740

Gnomad ASJ exome

AF:

0.803

Gnomad EAS exome

AF:

0.273

Gnomad FIN exome

AF:

0.737

Gnomad NFE exome

AF:

0.785

Gnomad OTH exome

AF:

0.729

GnomAD4 exome

AF:

0.756

AC:

1092526

AN:

1445944

Hom.:

422400

Cov.:

AF XY:

0.748

AC XY:

537179

AN XY:

718358

show subpopulations

African (AFR)

AF:

0.857

AC:

28015

AN:

32702

American (AMR)

AF:

0.744

AC:

31927

AN:

42934

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

20670

AN:

25636

East Asian (EAS)

AF:

0.266

AC:

10521

AN:

39530

South Asian (SAS)

AF:

0.494

AC:

41512

AN:

84042

European-Finnish (FIN)

AF:

0.734

AC:

38856

AN:

52942

Middle Eastern (MID)

AF:

0.680

AC:

3873

AN:

5694

European-Non Finnish (NFE)

AF:

0.792

AC:

873118

AN:

1102758

Other (OTH)

AF:

0.738

AC:

44034

AN:

59706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

13919

27838

41757

55676

69595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20402

40804

61206

81608

102010

<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:

0.769

AC:

117060

AN:

152128

Hom.:

46113

Cov.:

AF XY:

0.760

AC XY:

56528

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.849

AC:

35254

AN:

41534

American (AMR)

AF:

0.773

AC:

11806

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.811

AC:

2813

AN:

3468

East Asian (EAS)

AF:

0.265

AC:

1367

AN:

5158

South Asian (SAS)

AF:

0.463

AC:

2229

AN:

4816

European-Finnish (FIN)

AF:

0.738

AC:

7796

AN:

10560

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.783

AC:

53266

AN:

67998

Other (OTH)

AF:

0.767

AC:

1620

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1286

2573

3859

5146

6432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.772

Hom.:

178434

Bravo

AF:

0.778

TwinsUK

AF:

0.793

AC:

2940

ALSPAC

AF:

0.796

AC:

3068

ESP6500AA

AF:

0.843

AC:

3708

ESP6500EA

AF:

0.782

AC:

6721

ExAC

AF:

0.703

AC:

85314

Asia WGS

AF:

0.399

AC:

1390

AN:

3474

ClinVar

ClinVar submissions

Significance: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)

Familial hypobetalipoproteinemia 1 (2)

Hypercholesterolemia, autosomal dominant, type B (2)

not provided (2)

Cardiovascular phenotype (1)

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

Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.13

(source)

DANN

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.015

MetaRNN

Benign

9.7e-7

MetaSVM

Benign

-0.97

PhyloP100

0.59

PrimateAI

Benign

0.33

PROVEAN

Benign

1.2

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

0.97

Vest4

0.017

MPC

0.035

ClinPred

0.0051

GERP RS

1.6

gMVP

0.065

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over