rs267607040

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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. G870C) has been classified as 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

Publications

92 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 29
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Schinzel-Giedion syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
intellectual disability-expressive aphasia-facial dysmorphism syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SETBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr18-44951948-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3377279.Status of the report is criteria_provided_single_submitter, 1 stars.

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 VariationId is 1035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3 link	c.2608G>A	p.Gly870Ser	missense_variant	Exon 4 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2 link	c.2608G>A	p.Gly870Ser	missense_variant	Exon 4 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251064

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000889

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

Sep 19, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PS4, PM1, PM2, PP3 -

Apr 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Royal Medical Services, Bahrain Defence Force Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:3

Mar 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). -

Jul 17, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Feb 09, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SETBP1-related disorder

Pathogenic:2

Aug 30, 2022

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

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

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over