rs1178702025

Variant names:

• chr18-44951912-G-A
• rs1178702025
• NM_015559.3:c.2572G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_015559.3(SETBP1):​c.2572G>A​(p.Glu858Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 13 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802
• PP5: Variant 18-44951912-G-A is Pathogenic according to our data. Variant chr18-44951912-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951912-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.2572G>A	p.Glu858Lys	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	c.2572G>A	p.Glu858Lys	missense_variant	Exon 4 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727220

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.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schinzel-Giedion syndrome Pathogenic:2

Jul 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM2_SUP -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with autosomal dominant intellectual disability 29 (MIM#616078) and Schinzel-Giedion midface retraction syndrome (MIM#269150), respectively. The former is caused by premature termination variants, whereas the latter is caused by missense variants resulting in increased SETBP1 protein stability. (PMIDs: 28346496, 32460883, 25217958). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as in at least five individuals, three of whom was proven to be de novo (PMID: 25363760, 33391157, Clinvar, DECIPHER). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Transcriptome analysis performed on an individual with atypical chronic myeloid leukemia who was heterozygous for this variant, demonstrated differential expression of SETBP1 target genes. However, the individual's full genotype is unknown, therefore the observed effects cannot be conclusively attributed to this variant (PMID: 23222956 ). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Jul 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25028416, 25356899, 23832012, 31332282, 23222956, 25306901, 24695057, 23443343, 24127063, 28191890, 24267886, 23020937, 21037274, 20436468, 18398855, 29796729, 26185647, 29925043, 27509124, 28346496, 25663181, 25217958, 28714951, 32005694, 33391157, 34638574, 28158286, 31785789, 27824329, 28485484, 35571021) -

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 858 of the SETBP1 protein (p.Glu858Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SETBP1-related conditions (PMID: 27824329, 32005694; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521296). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Nov 20, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2572G>A (p.E858K) alteration is located in exon 4 (coding exon 3) of the SETBP1 gene. This alteration results from a G to A substitution at nucleotide position 2572, causing the glutamic acid (E) at amino acid position 858 to be replaced by a lysine (K)._x000D_ _x000D_ for SETBP1-related neurodevelopmental disorder; however, its clinical significance for Schinzel-Giedion syndrome is uncertain. The SETBP1 c.2572G>A (p.E858K) alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with SETBP1-related neurodevelopmental disorder (De Rubeis, 2014; Leonardi; 2020; Dong, 2020; Chuan, 2022) including multiple de novo occurrences (DECIPHER v.9.32; external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Mar 02, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS5,PM1,PM2,PP3 -

Intellectual disability, autosomal dominant 29 Pathogenic:1

Dec 08, 2017

GenomeConnect - Simons Searchlight

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-12-08 and interpreted as Likely Pathogenic. Variant was initially reported on 2017-08-07 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.24		Gain of ubiquitination at E858 (P = 0.0011);Gain of ubiquitination at E858 (P = 0.0011);
MVP		0.90
MPC		0.97
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.70

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: rs1178702025; hg19: chr18-42531877; COSMIC: COSV56312188;