chr18-45063547-C-T

Variant names:

• chr18-45063547-C-T
• rs201973930
• NM_015559.3:c.4640C>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.4640C>T​(p.Thr1547Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000077 in 129,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1547N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000077 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 1 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

ENSG00000267101 (HGNC:):

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=0.1516222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.4640C>T	p.Thr1547Ile	missense_variant	Exon 6 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.4640C>T	p.Thr1547Ile	missense_variant	Exon 6 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.00000770 AC: 1 AN: 129806 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000291

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1239052 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 610906

African (AFR) AF: 0.00 AC: 0 AN: 26726

American (AMR) AF: 0.00 AC: 0 AN: 29578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20244

East Asian (EAS) AF: 0.00 AC: 0 AN: 31172

South Asian (SAS) AF: 0.00 AC: 0 AN: 67628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3488

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 964446

Other (OTH) AF: 0.00 AC: 0 AN: 50846

GnomAD4 genome AF: 0.00000770 AC: 1 AN: 129806 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 62358

African (AFR) AF: 0.0000291 AC: 1 AN: 34368

American (AMR) AF: 0.00 AC: 0 AN: 11776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3138

East Asian (EAS) AF: 0.00 AC: 0 AN: 4382

South Asian (SAS) AF: 0.00 AC: 0 AN: 3946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61356

Other (OTH) AF: 0.00 AC: 0 AN: 1712

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.51	.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		1.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.50	.;N
REVEL	Benign	0.039
Sift	Benign	0.20	.;T
Sift4G	Uncertain	0.044	.;D
Polyphen		0.13	B;B
Vest4		0.077
MutPred		0.20		Loss of phosphorylation at T1547 (P = 0.0031);Loss of phosphorylation at T1547 (P = 0.0031);
MVP		0.26
MPC		1.4
ClinPred		0.56	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.19
Mutation Taster		=89/11	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: rs201973930; hg19: chr18-42643512;