rs679899

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.1853C>T(p.Ala618Val) variant causes a missense change. The variant allele was found at a frequency of 0.47 in 1,608,604 control chromosomes in the GnomAD database, including 187,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 14276 hom., cov: 32)

Exomes 𝑓: 0.48 ( 172976 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 6.75

Publications

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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.0775246E-6).

BP6

Variant 2-21028042-G-A is Benign according to our data. Variant chr2-21028042-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.1853C>T	p.Ala618Val	missense_variant	Exon 14 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.1853C>T	p.Ala618Val	missense_variant	Exon 14 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60939

AN:

151950

Hom.:

14286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.358

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.372

Gnomad EAS

AF:

0.853

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.469

Gnomad OTH

AF:

0.421

GnomAD2 exomes

AF:

0.490

AC:

123023

AN:

251266

AF XY:

0.501

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.395

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.852

Gnomad FIN exome

AF:

0.568

Gnomad NFE exome

AF:

0.469

Gnomad OTH exome

AF:

0.469

GnomAD4 exome

AF:

0.477

AC:

694384

AN:

1456536

Hom.:

172976

Cov.:

AF XY:

0.482

AC XY:

349457

AN XY:

724912

show subpopulations

African (AFR)

AF:

0.159

AC:

5308

AN:

33404

American (AMR)

AF:

0.390

AC:

17442

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

9652

AN:

26116

East Asian (EAS)

AF:

0.863

AC:

34245

AN:

39664

South Asian (SAS)

AF:

0.610

AC:

52510

AN:

86122

European-Finnish (FIN)

AF:

0.558

AC:

29791

AN:

53402

Middle Eastern (MID)

AF:

0.457

AC:

2628

AN:

5752

European-Non Finnish (NFE)

AF:

0.465

AC:

514456

AN:

1107122

Other (OTH)

AF:

0.471

AC:

28352

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

17411

34822

52232

69643

87054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15286

30572

45858

61144

76430

<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:

0.401

AC:

60920

AN:

152068

Hom.:

14276

Cov.:

AF XY:

0.410

AC XY:

30508

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.174

AC:

7231

AN:

41492

American (AMR)

AF:

0.377

AC:

5760

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.372

AC:

1289

AN:

3468

East Asian (EAS)

AF:

0.853

AC:

4410

AN:

5172

South Asian (SAS)

AF:

0.624

AC:

3010

AN:

4820

European-Finnish (FIN)

AF:

0.571

AC:

6040

AN:

10572

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.469

AC:

31848

AN:

67946

Other (OTH)

AF:

0.424

AC:

894

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1665

3331

4996

6662

8327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.454

Hom.:

74810

Bravo

AF:

0.372

TwinsUK

AF:

0.460

AC:

1706

ALSPAC

AF:

0.475

AC:

1829

ESP6500AA

AF:

0.177

AC:

779

ESP6500EA

AF:

0.462

AC:

3975

ExAC

AF:

0.485

AC:

58942

Asia WGS

AF:

0.694

AC:

2411

AN:

3478

EpiCase

AF:

0.470

EpiControl

AF:

0.469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Oct 18, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:4

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypobetalipoproteinemia 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:2

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 19, 2024

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Dec 08, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Warfarin response

Other:1

Aug 31, 2010

Pharmacogenomics Lab, Chungbuk National University

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

In patients receiving warfarin after mechanical valve replacement, G allele carriers of rs679899 had 6.4 times increased risk of bleeding. likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.079

.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

.;T

MetaRNN

Benign

0.0000021

T;T

MetaSVM

Benign

-0.93

PhyloP100

6.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

N;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0050

D;T

Sift4G

Pathogenic

0.0

D;D

Vest4

0.55

MPC

0.27

ClinPred

0.016

GERP RS

5.7

gMVP

0.68

Mutation Taster

=65/35

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over