rs606231273
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015559.3(SETBP1):c.1876C>T(p.Arg626Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R626R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015559.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETBP1 | NM_015559.3 | c.1876C>T | p.Arg626Ter | stop_gained | 4/6 | ENST00000649279.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETBP1 | ENST00000649279.2 | c.1876C>T | p.Arg626Ter | stop_gained | 4/6 | NM_015559.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 38
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 29 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Apr 06, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. Variant was initially reported on 2017-06-20 by GTR ID of laboratory name Radbound UMC . The reporting laboratory might also submit to ClinVar. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2023 | 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34490615, 33907317, 25217958) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | This premature translational stop signal has been observed in individual(s) with clinical features of SETBP1-related conditions (PMID: 25217958, 33907317, 34490615). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 157560). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg626*) in the SETBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETBP1 are known to be pathogenic (PMID: 21037274, 25217958). - |
Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
SETBP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The SETBP1 c.1876C>T variant is predicted to result in premature protein termination (p.Arg626*). This variant was reported in an individual with neurodevelopmental disorder (Coe. 2014. PubMed ID: 25217958; Morgan. 2021. PubMed ID: 33907317; van der Ven. 2021. PubMed ID: 34490615). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SETBP1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at