2-21016488-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
The NM_000384.3(APOB):c.3283G>A(p.Asp1095Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,611,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
APOB
NM_000384.3 missense
NM_000384.3 missense
Scores
6
2
8
Clinical Significance
Conservation
PhyloP100: 5.63
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.812
BP6
Variant 2-21016488-C-T is Benign according to our data. Variant chr2-21016488-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544067.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.3283G>A | p.Asp1095Asn | missense_variant | 21/29 | 1 | NM_000384.3 | ENSP00000233242.1 | ||
APOB | ENST00000673739.2 | n.*2589G>A | non_coding_transcript_exon_variant | 20/25 | ENSP00000501110.2 | |||||
APOB | ENST00000673739.2 | n.*2589G>A | 3_prime_UTR_variant | 20/25 | ENSP00000501110.2 | |||||
APOB | ENST00000673882.2 | n.*2428-943G>A | intron_variant | ENSP00000501253.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251432Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459818Hom.: 0 Cov.: 29 AF XY: 0.00000964 AC XY: 7AN XY: 726350
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 22, 2023 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of MoRF binding (P = 0.053);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at