chr2-21019754-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000384.3(APOB):c.2968G>A(p.Ala990Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.2968G>A | p.Ala990Thr | missense_variant | 19/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.2968G>A | p.Ala990Thr | missense_variant | 19/29 | 1 | NM_000384.3 | P1 | |
APOB | ENST00000673739.2 | c.*2274G>A | 3_prime_UTR_variant, NMD_transcript_variant | 18/25 | |||||
APOB | ENST00000673882.2 | c.*2274G>A | 3_prime_UTR_variant, NMD_transcript_variant | 18/23 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251218Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135814
GnomAD4 exome AF: 0.0000711 AC: 104AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727228
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74290
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 31, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Hypercholesterolemia, familial, 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
Hypercholesterolemia, autosomal dominant, type B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Familial hypobetalipoproteinemia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2023 | The p.A990T variant (also known as c.2968G>A), located in coding exon 19 of the APOB gene, results from a G to A substitution at nucleotide position 2968. The alanine at codon 990 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at