Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_015559.3(SETBP1):c.2614G>A(p.Gly872Arg) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G872G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.97

Publications

3 publications found

Variant links:

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]

SETBP1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 29
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Schinzel-Giedion syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
intellectual disability-expressive aphasia-facial dysmorphism syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SETBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_015559.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 18-44951954-G-A is Pathogenic according to our data. Variant chr18-44951954-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523513.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETBP1	NM_015559.3	MANE Select	c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	NP_056374.2
SETBP1	NM_001379141.1		c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	NP_001366070.1
SETBP1	NM_001379142.1		c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	NP_001366071.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETBP1	ENST00000649279.2	MANE Select	c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	ENSP00000497406.1
SETBP1	ENST00000677068.1		c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	ENSP00000504398.1
SETBP1	ENST00000677077.1		c.2614G>A	p.Gly872Arg	missense	Exon 4 of 6	ENSP00000503656.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atrial septal defect;C0020295:Hydronephrosis;C0039538:Teratoma;C0235946:Cerebral atrophy;C0456132:Large fontanelles;C0853087:Abnormal nail morphology;C1691215:Penile hypospadias;C1853242:Midface retrusion (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

2.0

PhyloP100

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.32

Gain of catalytic residue at G872 (P = 0.0397)

MVP

0.94

MPC

1.0

ClinPred

0.98

GERP RS

6.2

Varity_R

0.95

gMVP

0.73

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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rs1555706928

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over