rs606231273
Positions:
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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SETBP1
NM_015559.3 stop_gained
NM_015559.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.69
Genes affected
SETBP1 (HGNC:15573): (SET binding protein 1) This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The encoded protein has been shown to bind the SET nuclear oncogene which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-44951216-C-T is Pathogenic according to our data. Variant chr18-44951216-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 157560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951216-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SETBP1 | NM_015559.3 | c.1876C>T | p.Arg626Ter | stop_gained | 4/6 | ENST00000649279.2 | NP_056374.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SETBP1 | ENST00000649279.2 | c.1876C>T | p.Arg626Ter | stop_gained | 4/6 | NM_015559.3 | ENSP00000497406 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 29 Pathogenic:2
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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | 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, no assertion criteria provided | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
0.87
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at