rs267607040

Positions:

• chr18-44951948-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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. G870D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 1 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 chr18-44951949-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1034.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 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	UniProt
SETBP1	NM_015559.3	c.2608G>A	p.Gly870Ser	missense_variant	4/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.2608G>A	p.Gly870Ser	missense_variant	4/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

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.: 32

Alfa AF: 0.00152 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schinzel-Giedion syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2011	- -
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, 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	Revvity Omics, Revvity	Feb 09, 2021	- -
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	Invitae	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. -

SETBP1-related disorder Pathogenic:2

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. -
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. -

Chronic myelogenous leukemia, BCR-ABL1 positive Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	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	D
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

Other links and lift over

dbSNP: rs267607040; hg19: chr18-42531913; COSMIC: COSV56311834;