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GeneBe

rs693

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000384.3(APOB):c.7545C>T(p.Thr2515=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,613,650 control chromosomes in the GnomAD database, including 181,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 12425 hom., cov: 32)
Exomes 𝑓: 0.47 ( 168652 hom. )

Consequence

APOB
NM_000384.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 0.126
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 2-21009323-G-A is Benign according to our data. Variant chr2-21009323-G-A is described in ClinVar as [Benign]. Clinvar id is 128425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21009323-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.126 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APOBNM_000384.3 linkuse as main transcriptc.7545C>T p.Thr2515= synonymous_variant 26/29 ENST00000233242.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOBENST00000233242.5 linkuse as main transcriptc.7545C>T p.Thr2515= synonymous_variant 26/291 NM_000384.3 P1

Frequencies

GnomAD3 genomes
AF:
0.381
AC:
57860
AN:
151844
Hom.:
12425
Cov.:
32
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
GnomAD3 exomes
AF:
0.389
AC:
97584
AN:
251146
Hom.:
21368
AF XY:
0.391
AC XY:
53030
AN XY:
135726
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 SAS exome
AF:
0.267
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.:
66
AF XY:
0.462
AC XY:
335706
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.209
Gnomad4 AMR exome
AF:
0.382
Gnomad4 ASJ exome
AF:
0.353
Gnomad4 EAS exome
AF:
0.0530
Gnomad4 SAS exome
AF:
0.273
Gnomad4 FIN exome
AF:
0.411
Gnomad4 NFE exome
AF:
0.517
Gnomad4 OTH exome
AF:
0.428
GnomAD4 genome
AF:
0.381
AC:
57866
AN:
151962
Hom.:
12425
Cov.:
32
AF XY:
0.372
AC XY:
27619
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.229
Gnomad4 AMR
AF:
0.413
Gnomad4 ASJ
AF:
0.356
Gnomad4 EAS
AF:
0.0546
Gnomad4 SAS
AF:
0.247
Gnomad4 FIN
AF:
0.386
Gnomad4 NFE
AF:
0.500
Gnomad4 OTH
AF:
0.370
Alfa
AF:
0.459
Hom.:
29043
Bravo
AF:
0.375
Asia WGS
AF:
0.165
AC:
578
AN:
3478
EpiCase
AF:
0.486
EpiControl
AF:
0.485

ClinVar

Significance: Benign
Submissions summary: Benign:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-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. -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 07, 2016This 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. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Hypercholesterolemia, autosomal dominant, type B Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Familial hypobetalipoproteinemia 1 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Hypercholesterolemia, familial, 1 Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 27, 2017- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 10, 2015This alteration is classified as benign based on a combination of the following: 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. -
Familial hypercholesterolemia Benign:1
Benign, no assertion criteria providedclinical testingCohesion PhenomicsSep 19, 2022- -
Warfarin response Other:1
drug response, no assertion criteria providedresearchPharmacogenomics Lab, Chungbuk National UniversityAug 31, 2010- likely responsive

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
Cadd
Benign
5.1
Dann
Benign
0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs693; hg19: chr2-21232195; COSMIC: COSV51935946; API