rs606231272

Positions:

• chr18-44951213-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015559.3(SETBP1):​c.1873C>T​(p.Arg625*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETBP1 NM_015559.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.51

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-44951213-C-T is Pathogenic according to our data. Variant chr18-44951213-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 157559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951213-C-T is described in Lovd as [Likely_pathogenic]. Variant chr18-44951213-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.1873C>T	p.Arg625*	stop_gained	4/6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.1873C>T	p.Arg625*	stop_gained	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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 29 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Nov 26, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-11-26 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 05-15-2018 by Lab or GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25217958, 27535533, 31785789, 26350204, 33907317) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 157559). This premature translational stop signal has been observed in individual(s) with SETBP1-related conditions (PMID: 25217958, 26350204). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg625*) in the SETBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETBP1 are known to be pathogenic (PMID: 21037274, 25217958). -

Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Jan 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM2_Supporting+PS4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.83
GERP RS		3.7

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: rs606231272; hg19: chr18-42531178; COSMIC: COSV56321163;