chr18-44951952-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_015559.3(SETBP1):c.2612T>C(p.Ile871Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I871S) has been classified as Pathogenic.
Frequency
Consequence
NM_015559.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETBP1 | NM_015559.3 | c.2612T>C | p.Ile871Thr | missense_variant | 4/6 | ENST00000649279.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETBP1 | ENST00000649279.2 | c.2612T>C | p.Ile871Thr | missense_variant | 4/6 | NM_015559.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251080Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135792
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Schinzel-Giedion syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo change in individuals with Schinzel-Giedion syndrome (SGS) (PMID: 28346496, 20436468, 22473152, 31680123). This variant is located in a 12-base pair hotspot region for pathogenic variation associated with SGS (PMID: 28346496). Functional studies have shown that this variant is associated with an increase in protein levels compared to wild type SETBP1 (PMID: 28346496). The c.2612T>C (p.Ile871Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/251080). However, this gene may be prone to somatic variation (PMID: 34906245, 28346496) and it is not known if the variants observed in gnomAD represent germline or somatic events. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.2612T>C (p.Ile871Thr) is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 27, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Pathogenic, for Schinzel-Giedion midface retraction syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (PMID:20436468). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple unrelated patients. (PMID:20436468,25028416). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:28346496). - |
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2023 | Published functional studies demonstrate that the I871T variant alters SETBP1 function in vitro (Acuna-Hidalgo et al., 2017; Makishima et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23832012, 31680123, 20436468, 28346496, 22473152, 25028416, 27535533, 34782754) - |
Intellectual disability, autosomal dominant 29 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 24, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Schinzel-Giedion midface retraction syndrome [PMID 20436468, 28346496] - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Sep 27, 2018 | - - |
Fetal akinesia deformation sequence 1;C5779613:Arthrogryposis multiplex congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Cirak Lab, University Hospital Cologne | Jun 28, 2019 | - - |
SETBP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2024 | The SETBP1 c.2612T>C variant is predicted to result in the amino acid substitution p.Ile871Thr. This variant has been reported to occur de novo in more than 14 individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Lestner et al. 2012. PubMed ID: 22473152; Miyake et al. 2015. PubMed ID: 25028416; Takeuchi et al. 2015. PubMed ID: 26096993; Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). Functional studies suggested that the p.Ile871Thr variant confers increased protein stability, supporting the gain-of-function disease mechanism in Schinzel-Giedion syndrome (Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at