rs267607042

chr18-44951942-G-Achr18-44951942-G-Cchr18-44951942-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_015559.3(SETBP1):c.2602G>A(p.Asp868Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D868A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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 14 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 chr18-44951942-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 18-44951942-G-A is Pathogenic according to our data. Variant chr18-44951942-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44951942-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3	c.2602G>A	p.Asp868Asn	missense_variant	4/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.2602G>A	p.Asp868Asn	missense_variant	4/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schinzel-Giedion syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 12, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	Functional studies demonstrated that p.(D868N) is associated with significantly increased levels of SETBP1 protein expression compared to wildtype (Acuna-Hidalgo et al., 2017).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25663181, 28774369, 28346496, 31216405, 32005694, 25852444, 20436468) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2017	- -

SETBP1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2022

The SETBP1 c.2602G>A variant is predicted to result in the amino acid substitution p.Asp868Asn. This variant has been reported as a recurrent de novo variant in individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Case 1, Volk et al. 2015. PubMed ID: 25852444). In addition, other variants impacting the same amino acid (p.Asp868Ala and p.Asp868Tyr) have also been reported in individuals with Schinzel-Giedion syndrome (Hoischen et al. 2010. PubMed ID: 20436468; Supplemental Data, Case 15, Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant, and other variants impacting this same amino acid, have also been reported as somatic variants in individuals with various leukemias (Supplemental Data, Acuna-Hidalgo et al. 2017. PubMed ID: 28346496). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, this variant is interpreted as pathogenic. -

Intellectual disability, autosomal dominant 29 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 12, 2022

- -

Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.29		Gain of glycosylation at S867 (P = 0.1166);Gain of glycosylation at S867 (P = 0.1166);
MVP		0.88
MPC		0.90
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.84
gMVP		0.72

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: rs267607042; hg19: chr18-42531907; COSMIC: COSV56311800;