chr18-44701432-C-T

Variant names:

• chr18-44701432-C-T
• rs1292543210
• NM_015559.3:c.86C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015559.3(SETBP1):​c.86C>T​(p.Ala29Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,452,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A29T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086511105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.86C>T	p.Ala29Val	missense_variant	Exon 2 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.86C>T	p.Ala29Val	missense_variant	Exon 2 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452548 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721438

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 43162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 85174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1106906

Other (OTH) AF: 0.00 AC: 0 AN: 60058

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with SETBP1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1501041). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 29 of the SETBP1 protein (p.Ala29Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.77	T;.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.087	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;N;.;.
PhyloP100		4.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;.;N;.;.
REVEL	Benign	0.086
Sift	Benign	0.086	T;.;T;.;.
Sift4G	Benign	0.096	T;.;D;T;.
Polyphen		0.0020	B;B;B;.;.
Vest4		0.17
MutPred		0.076		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.15
MPC		0.27
ClinPred		0.43	T
GERP RS		3.8
Varity_R		0.079
gMVP		0.10
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1292543210; hg19: chr18-42281397;