NM_000384.3:c.12739C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000384.3(APOB):c.12739C>T(p.Gln4247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,574 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 Uncertain significance (★★).
Frequency
Consequence
NM_000384.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250738Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135514
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461488Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10AN XY: 727062
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74276
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:2
This sequence change creates a premature translational stop signal (p.Gln4247*) in the APOB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 317 amino acid(s) of the APOB protein. This variant is present in population databases (no rsID available, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 33418990). ClinVar contains an entry for this variant (Variation ID: 544074). This variant disrupts a region of the APOB protein in which other variant(s) (p.Tyr4380*) have been observed in individuals with APOB-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
- -
APOB-related disorder Uncertain:1
The APOB c.12739C>T (p.Gln4247Ter) variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. This variant is located in the last exon and may escape nonsense-mediated decay. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for APOB-related disorders. -
not provided Uncertain:1
- -
Cardiovascular phenotype Uncertain:1
The p.Q4247* variant (also known as c.12739C>T), located in coding exon 29 of the APOB gene, results from a C to T substitution at nucleotide position 12739. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This alteration has been reported in a familial hypercholesterolemia (FH) cohort (Meshkov A et al. Genes (Basel), 2021 01;12:). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of APOB has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at