chr18-44869236-A-G

Variant names:

• chr18-44869236-A-G
• rs770804298
• NM_015559.3:c.493A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015559.3(SETBP1):​c.493A>G​(p.Thr165Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. T165I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.116
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054765552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.493A>G	p.Thr165Ala	missense_variant	Exon 3 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.493A>G	p.Thr165Ala	missense_variant	Exon 3 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251196 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461760 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 16, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.67
DEOGEN2	Benign	0.12	.;T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.38	T;.;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N;.
PhyloP100		0.12
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.59	N;.;N;.
REVEL	Benign	0.094
Sift	Benign	0.15	T;.;T;.
Sift4G	Benign	0.58	T;.;T;.
Polyphen		0.0040	B;B;B;.
Vest4		0.15
MutPred		0.16		Loss of phosphorylation at T165 (P = 0.0171);Loss of phosphorylation at T165 (P = 0.0171);Loss of phosphorylation at T165 (P = 0.0171);Loss of phosphorylation at T165 (P = 0.0171);
MVP		0.10
MPC		0.25
ClinPred		0.054	T
GERP RS		-2.3
Varity_R		0.032
gMVP		0.14
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs770804298; hg19: chr18-42449201;