rs267607038

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

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).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:1

Conservation

PhyloP100: 7.99

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]

SETBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest Disordered (size 35) in uniprot entity SETBP_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_015559.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

PP5

Variant 18-44951952-T-C is Pathogenic according to our data. Variant chr18-44951952-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1031.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=8}. Variant chr18-44951952-T-C is described in Lovd as [Pathogenic]. Variant chr18-44951952-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETBP1	NM_015559.3 linkuse as main transcript	c.2612T>C	p.Ile871Thr	missense_variant	4/6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2 linkuse as main transcript	c.2612T>C	p.Ile871Thr	missense_variant	4/6		NM_015559.3	ENSP00000497406	P2	Q9Y6X0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251080

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Schinzel-Giedion syndrome

Pathogenic:5

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	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	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

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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 21, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

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, no assertion criteria provided

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.8

.;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.27

Loss of stability (P = 0.002);Loss of stability (P = 0.002);

MVP

0.95

MPC

1.0

ClinPred

0.98

GERP RS

6.2

Varity_R

0.76

gMVP

0.54

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over