rs267607042
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_015559.3(SETBP1):c.2602G>A(p.Asp868Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D868A) has been classified as Pathogenic.
Frequency
Consequence
NM_015559.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETBP1 | NM_015559.3 | c.2602G>A | p.Asp868Asn | missense_variant | 4/6 | ENST00000649279.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETBP1 | ENST00000649279.2 | c.2602G>A | p.Asp868Asn | missense_variant | 4/6 | NM_015559.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461880Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3AN XY: 727234
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74212
ClinVar
Submissions by phenotype
Schinzel-Giedion syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 12, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2010 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2023 | Functional studies demonstrated that p.(D868N) is associated with significantly increased levels of SETBP1 protein expression compared to wildtype (Acuna-Hidalgo et al., 2017).; Not observed at significant frequency in large population cohorts (gnomAD); 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: 25663181, 28774369, 28346496, 31216405, 32005694, 25852444, 20436468) - |
Intellectual disability, autosomal dominant 29 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 12, 2022 | - - |
Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2017 | - - |
SETBP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2022 | The SETBP1 c.2602G>A variant is predicted to result in the amino acid substitution p.Asp868Asn. This variant has been reported as a recurrent de novo variant in individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Case 1, Volk et al. 2015. PubMed ID: 25852444). In addition, other variants impacting the same amino acid (p.Asp868Ala and p.Asp868Tyr) have also been reported in individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Supplemental Data, Case 15, Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant, and other variants impacting this same amino acid, have also been reported as somatic variants in individuals with various leukemias (Supplemental Data, Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at