rs766243954
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000384.3(APOB):c.409G>T(p.Glu137*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,026 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000384.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.409G>T | p.Glu137* | stop_gained | Exon 5 of 29 | 1 | NM_000384.3 | ENSP00000233242.1 | ||
APOB | ENST00000399256.4 | c.409G>T | p.Glu137* | stop_gained | Exon 5 of 17 | 1 | ENSP00000382200.4 | |||
APOB | ENST00000673739.2 | n.384-831G>T | intron_variant | Intron 4 of 24 | ENSP00000501110.2 | |||||
APOB | ENST00000673882.2 | n.384-831G>T | intron_variant | Intron 4 of 22 | ENSP00000501253.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727220
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 10, 2024 | This sequence change creates a premature translational stop signal (p.Glu137*) in the APOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APOB are known to be pathogenic (PMID: 20032471). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypobetalipoproteinemia (PMID: 34340953). ClinVar contains an entry for this variant (Variation ID: 404400). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Nov 02, 2021 | Criteria Codes: PVS1 PM2 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32719484) - |
Familial hypobetalipoproteinemia 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Glu137Ter variant in APOB has not been previously reported in individuals with low LDL, but has been identified in 0.006483% (1/15424) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766243954). This variant has also been reported in ClinVar (VariationID: 404400) as pathogenic by Invitae and Fulgent Genetics. This nonsense variant leads to a premature termination codon at position 137, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the APOB gene is an established disease mechanism in low LDL. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu137Ter variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at