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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015559.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-44951942-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 18-44951942-G-A is Pathogenic according to our data. Variant chr18-44951942-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951942-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SETBP1NM_015559.3 linkuse as main transcriptc.2602G>A p.Asp868Asn missense_variant 4/6 ENST00000649279.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SETBP1ENST00000649279.2 linkuse as main transcriptc.2602G>A p.Asp868Asn missense_variant 4/6 NM_015559.3 P2Q9Y6X0-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151986
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461880
Hom.:
0
Cov.:
38
AF XY:
0.00000413
AC XY:
3
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151986
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74212
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Schinzel-Giedion syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 12, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2010- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 26, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 05, 2023Functional 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 submitterclinical testingBaylor GeneticsDec 12, 2022- -
Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 31, 2017- -
SETBP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 06, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.73
D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Benign
2.0
M;M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-4.8
.;D
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
.;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.29
Gain of glycosylation at S867 (P = 0.1166);Gain of glycosylation at S867 (P = 0.1166);
MVP
0.88
MPC
0.90
ClinPred
1.0
D
GERP RS
6.2
Varity_R
0.84
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267607042; hg19: chr18-42531907; COSMIC: COSV56311800; API