2-21002893-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000384.3(APOB):c.12529C>T(p.Arg4177Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,506 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). Synonymous variant affecting the same amino acid position (i.e. R4177R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000384.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.12529C>T | p.Arg4177Ter | stop_gained | 29/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.12529C>T | p.Arg4177Ter | stop_gained | 29/29 | 1 | NM_000384.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250528Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135370
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461460Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727010
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 23, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2019 | The p.R4177* variant (also known as c.12529C>T), located in coding exon 29 of the APOB gene, results from a C to T substitution at nucleotide position 12529. This changes the amino acid from an arginine to a stop codon within coding exon 29. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of APOB and is not expected to trigger nonsense-mediated mRNA decay. This alteration impacts the last 387 amino acids in the protein C-terminus, which has been indicated to play a role in both lipoprotein assembly and LDLR binding (McCormick SP et al. J. Biol. Chem., 1997 Sep;272:23616-22; Boren J et al. J. Clin. Invest., 1998 Mar;101:1084-93; Borén J et al. J. Biol. Chem., 2001 Mar;276:9214-8). Nevertheless, the exact functional impact of these altered amino acids is unknown at this time. 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 | Sep 23, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at