rs1801695

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.13441G>A(p.Ala4481Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,613,902 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. A4481A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 102 hom., cov: 32)

Exomes 𝑓: 0.032 ( 867 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.190

Publications

32 publications found

Variant links:

COSMIC-nc: COSV107232167

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

APOB links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000384.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020777583).

BP6

Variant 2-21001981-C-T is Benign according to our data. Variant chr2-21001981-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128419.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0561 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.13441G>A	p.Ala4481Thr	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.13441G>A	p.Ala4481Thr	missense	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3958

AN:

152084

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00623

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.0406

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0359

Gnomad OTH

AF:

0.0326

GnomAD2 exomes

AF:

0.0252

AC:

6310

AN:

250316

AF XY:

0.0262

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0317

AC:

46356

AN:

1461698

Hom.:

867

Cov.:

AF XY:

0.0317

AC XY:

23064

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33468

American (AMR)

AF:

0.0195

AC:

872

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

919

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39682

South Asian (SAS)

AF:

0.0206

AC:

1774

AN:

86254

European-Finnish (FIN)

AF:

0.0215

AC:

1146

AN:

53348

Middle Eastern (MID)

AF:

0.0614

AC:

354

AN:

5768

European-Non Finnish (NFE)

AF:

0.0354

AC:

39341

AN:

1111940

Other (OTH)

AF:

0.0287

AC:

1736

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2624

5248

7872

10496

13120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<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:

0.0260

AC:

3957

AN:

152204

Hom.:

102

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00621

AC:

258

AN:

41526

American (AMR)

AF:

0.0406

AC:

621

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0205

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0238

AC:

252

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0359

AC:

2442

AN:

68010

Other (OTH)

AF:

0.0322

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

197

393

590

786

983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0321

Hom.:

257

Bravo

AF:

0.0255

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0427

EpiControl

AF:

0.0386

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Hypercholesterolemia, familial, 1 (4)

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

Benign

0.092

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.3

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.41

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PhyloP100

0.19

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

REVEL

Benign

0.033

Sift

Benign

0.15

Sift4G

Benign

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.094

Mutation Taster

=89/11

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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