rs606231273

Positions:

• chr18-44951216-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.1876C>T​(p.Arg626*) 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:6
• Conservation: PhyloP100: 2.69

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 18-44951216-C-T is Pathogenic according to our data. Variant chr18-44951216-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 157560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951216-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.1876C>T	p.Arg626*	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.1876C>T	p.Arg626*	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 29 Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Apr 06, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. Variant was initially reported on 2017-06-20 by GTR ID of laboratory name Radbound UMC . The reporting laboratory might also submit to ClinVar. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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: 34490615, 33907317, 25217958) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2023	This premature translational stop signal has been observed in individual(s) with clinical features of SETBP1-related conditions (PMID: 25217958, 33907317, 34490615). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 157560). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg626*) 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

SETBP1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The SETBP1 c.1876C>T variant is predicted to result in premature protein termination (p.Arg626*). This variant was reported in an individual with neurodevelopmental disorder (Coe. 2014. PubMed ID: 25217958; Morgan. 2021. PubMed ID: 33907317; van der Ven. 2021. PubMed ID: 34490615). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SETBP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.87
GERP RS		4.1

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: rs606231273; hg19: chr18-42531181; COSMIC: COSV56329952;