rs693

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -17 ACMG points: 0P and 17B. BA1BP4_StrongBP6_StrongBP7

The NM_000384.3(APOB):c.7545C>T (p.Thr2515Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.459 (AC=741,095) in the gnomAD database across 1,613,650 control chromosomes, including 181,077 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.516. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 12425 hom., cov: 32)

Exomes 𝑓: 0.47 ( 168652 hom. )

Consequence

APOB
NM_000384.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.126

Publications

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5157 — exceeds 5%% threshold (BA1 applied)

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.7545C>T	p.Thr2515Thr	synonymous	Exon 26 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.7545C>T	p.Thr2515Thr	synonymous	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57860

AN:

151844

Hom.:

12425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.534

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.0547

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.389

AC:

97584

AN:

251146

AF XY:

0.391

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.381

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.0572

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.418

GnomAD4 exome

AF:

0.467

AC:

683229

AN:

1461688

Hom.:

168652

Cov.:

AF XY:

0.462

AC XY:

335706

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.209

AC:

7008

AN:

33468

American (AMR)

AF:

0.382

AC:

17057

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

9217

AN:

26130

East Asian (EAS)

AF:

0.0530

AC:

2103

AN:

39696

South Asian (SAS)

AF:

0.273

AC:

23509

AN:

86248

European-Finnish (FIN)

AF:

0.411

AC:

21932

AN:

53404

Middle Eastern (MID)

AF:

0.334

AC:

1927

AN:

5768

European-Non Finnish (NFE)

AF:

0.517

AC:

574621

AN:

1111878

Other (OTH)

AF:

0.428

AC:

25855

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22072

44143

66215

88286

110358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16186

32372

48558

64744

80930

<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:

0.381

AC:

57866

AN:

151962

Hom.:

12425

Cov.:

AF XY:

0.372

AC XY:

27619

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.229

AC:

9477

AN:

41448

American (AMR)

AF:

0.413

AC:

6303

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1231

AN:

3462

East Asian (EAS)

AF:

0.0546

AC:

283

AN:

5182

South Asian (SAS)

AF:

0.247

AC:

1186

AN:

4804

European-Finnish (FIN)

AF:

0.386

AC:

4067

AN:

10540

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.500

AC:

33953

AN:

67940

Other (OTH)

AF:

0.370

AC:

781

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1722

3443

5165

6886

8608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.449

Hom.:

58449

Bravo

AF:

0.375

Asia WGS

AF:

0.165

AC:

578

AN:

3478

EpiCase

AF:

0.486

EpiControl

AF:

0.485

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0419

AC:

5131

AN:

122584

Turkish Variome

AF:

0.365

AC:

2454

AN:

6718

Hom.:

456

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0545

AC:

488

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.394

AC:

923

AN:

2342

Hom.:

186

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

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)

Hypercholesterolemia, familial, 1 (1)

Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.1

(source)

DANN

Benign

0.86

PhyloP100

0.13

Mutation Taster

=98/2

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over