rs267607039

Positions:

• chr18-44951949-G-A
• chr18-44951949-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_015559.3(SETBP1):​c.2609G>A​(p.Gly870Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 10 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
• 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, 0.863
• PP5: Variant 18-44951949-G-A is Pathogenic according to our data. 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. Variant chr18-44951949-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.2609G>A	p.Gly870Asp	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	c.2609G>A	p.Gly870Asp	missense_variant	4/6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Schinzel-Giedion syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 22, 2024	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 glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants that is known to be associated with Schinzel-Giedion syndrome (DECIPHER, PMID: 28346496) (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Gly870Ser) has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo in individuals with Schinzel-Giedion syndrome (PMID: 28346496). p.(Gly870Cys) has been observed in one individual with Schinzel-Giedion syndrome (PMID: 32460883). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as de novo in at least four individuals with Schinzel-Giedion syndrome (DECIPHER, PMIDs: 28346496, 20436468). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.7	.;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.33		Loss of catalytic residue at P866 (P = 0.071);Loss of catalytic residue at P866 (P = 0.071);
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.95
gMVP		0.69

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: rs267607039; hg19: chr18-42531914;