rs267607040

Positions:

chr18-44951948-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_015559.3(SETBP1):c.2608G>A(p.Gly870Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G870R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

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]

SETBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a compositionally_biased_region Polar residues (size 28) 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

PP5

Variant 18-44951948-G-A is Pathogenic according to our data. Variant chr18-44951948-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951948-G-A is described in Lovd as [Pathogenic]. Variant chr18-44951948-G-A 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.2608G>A	p.Gly870Ser	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.2608G>A	p.Gly870Ser	missense_variant	4/6		NM_015559.3	ENSP00000497406	P2	Q9Y6X0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00152

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schinzel-Giedion syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	In-silico analysis tools (REVEL, CADD, and FATHMM) predict the variant to be disease-causing and affect the SETBP1 protein function. Heterozygous variants in SETBP1 are associated with the intellectual developmental disorder, autosomal dominant 29 (MIM# 616078) and Schinzel-Giedion midface retraction syndrome (MIM# 269150). The above-mentioned variant is a recurrent variant in individuals with Schinzel-Giedion midface retraction syndrome (Hoischen et al.,2010). Also, this variant was reported in the ClinVar database as a pathogenic variant in nine independent submissions (variation id. 1035). -
Pathogenic, criteria provided, single submitter	clinical testing	Royal Medical Services, Bahrain Defence Force Hospital	-	The SETBP1 variant c.2608G>A p.(Gly870Ser) causes an amino acid change from Gly to Ser at position 870. According to HGMD Professional 2022.1, this variant has previously been described as disease causing for Schinzel-Giedion syndrome by Hoischen et al., 2010 (PMID: 20436468), Suphapeetiporn et al., 2011 (PMID: 21371013), Ko et al., 2013 (PMID: 23400866). ClinVar lists this variant (Interpretation: Pathogenic; Variation ID: 1035). It is classified as pathogenic (class 1) according to the recommendations of CENTOGENE and ACMG. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23222956). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001035 / PMID: 20436468). Different missense changes at the same codon (p.Gly870Asp, p.Gly870Cys) have been reported to be associated with SETBP1 related disorder (ClinVar ID: VCV000001034 / PMID: 20436468, 25082129). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 07, 2020	ACMG codes:PS4, PM1, PM2, PP3 -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Published functional studies demonstrate a damaging effect (significant increase in cell proliferation) (Piazza et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20436468, 26188272, 21371013, 23400866, 29333303, 32460883, 18398855, Neupauerova2019[casereport], 28209656, 28881700, 28419882, 31692115, 33822276, 29549983, 29435294, 28346496, 23222956) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SETBP1 protein function. ClinVar contains an entry for this variant (Variation ID: 1035). This missense change has been observed in individual(s) with Schinzel-Giedion syndrome (PMID: 20436468, 21371013). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 870 of the SETBP1 protein (p.Gly870Ser). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2021	- -

SETBP1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 30, 2022	The SETBP1 c.2608G>A variant is predicted to result in the amino acid substitution p.Gly870Ser. This variant has been well-documented to be pathogenic for Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Acuna-Hidalgo et al. 2017. PubMed ID: 28346496. Table S1 and S4). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-42531913-G-A). This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	The c.2608G>A (p.Gly870Ser) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a de novo and heterozygous change in patients with Schinzel-Giedion syndrome (PMID: 20436468, 21371013, 23400866, 26188272, 28346496, 29333303, 32460883, 23222956). Functional studies indicate this variant may lead to higher amounts of SETBP1 protein (PMID: 23222956). The c.2608G>A (p.Gly870Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251064). The sequence data provided for the gnomAD entry shows the c.2608G>A (p.Gly870Ser) in only 12% of NGS reads in an individual reported to be over the age of 75, therefore, the gnomAD entry likely represents an age-related somatic event (PMID: 23222956, 23832012). 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.2608G>A (p.Gly870Ser) is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.7

.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.31

Gain of glycosylation at G870 (P = 0.0113);Gain of glycosylation at G870 (P = 0.0113);

MVP

0.97

MPC

0.91

ClinPred

1.0

GERP RS

6.2

Varity_R

0.93

gMVP

0.64

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