rs72653095
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000384.3(APOB):c.8462C>T(p.Pro2821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,940 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2821P) has been classified as Likely benign.
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.8462C>T | p.Pro2821Leu | missense_variant | 26/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.8462C>T | p.Pro2821Leu | missense_variant | 26/29 | 1 | NM_000384.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00298 AC: 453AN: 152028Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00406 AC: 1021AN: 251208Hom.: 6 AF XY: 0.00449 AC XY: 609AN XY: 135774
GnomAD4 exome AF: 0.00399 AC: 5831AN: 1461794Hom.: 14 Cov.: 37 AF XY: 0.00414 AC XY: 3010AN XY: 727204
GnomAD4 genome ? AF: 0.00298 AC: 454AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.00278 AC XY: 207AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2021 | This variant is associated with the following publications: (PMID: 22995991, 24503134, 20657596, 18710658, 19602640, 27884173, 27153395, 30526649) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | APOB: BP4, BS2 - |
Hypercholesterolemia, familial, 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Feb 13, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: High frequency - |
Familial hypobetalipoproteinemia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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. - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Hypercholesterolemia, autosomal dominant, type B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2016 | 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. - |
Familial hypercholesterolemia Benign:1
Benign, criteria provided, single submitter | clinical testing | GENinCode PLC | Nov 28, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at