rs137852989
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The ENST00000272286.4(ABCG8):āc.1974C>Gā(p.Tyr658Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,078 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).
Frequency
Consequence
ENST00000272286.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCG8 | NM_022437.3 | c.1974C>G | p.Tyr658Ter | stop_gained | 13/13 | ENST00000272286.4 | NP_071882.1 | |
ABCG8 | NM_001357321.2 | c.1971C>G | p.Tyr657Ter | stop_gained | 13/13 | NP_001344250.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCG8 | ENST00000272286.4 | c.1974C>G | p.Tyr658Ter | stop_gained | 13/13 | 1 | NM_022437.3 | ENSP00000272286 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251406Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135890
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727240
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74396
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 4969). This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 11099417). This variant is present in population databases (rs137852989, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Tyr658*) in the ABCG8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the ABCG8 protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 25, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 01, 2024 | PM2, PM3, PVS1_strong - |
Sitosterolemia 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 25, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
ABCG8-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 01, 2024 | The ABCG8 c.1974C>G variant is predicted to result in premature protein termination (p.Tyr658*). This variant has been reported in an individual with sitosterolemia, who also had a second ABCG8 premature termination variant (Berge et al. 2000. PubMed ID: 11099417). At PreventionGenetics, we have also observed the p.Tyr658* variant in the homozygous state in an individual with sitosterolemia. However, this variant is located just 15 amino acids upstream of the native termination codon, and no other premature termination variants have been reported downstream of this variant. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Sitosterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2024 | Variant summary: ABCG8 c.1974C>G (p.Tyr658X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 2.4e-05 in 251406 control chromosomes. c.1974C>G has been reported in the literature in individuals affected with Sitosterolemia (example: Mariano_2019 and Lu_2001). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11452359, 31893465, 35549507). ClinVar contains an entry for this variant (Variation ID: 4969). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at