NM_015559.3:c.4172-5254C>T

Variant names:

• chr18-45057825-C-T
• rs1868755
• NM_015559.3:c.4172-5254C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015559.3(SETBP1):​c.4172-5254C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,286 control chromosomes in the GnomAD database, including 1,194 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1194 hom., cov: 33)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.4172-5254C>T		intron_variant	Intron 5 of 5	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.4172-5254C>T		intron_variant	Intron 5 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16895 AN: 152168 Hom.: 1192 Cov.: 33

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0772

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.00750

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.111 AC: 16895 AN: 152286 Hom.: 1194 Cov.: 33 AF XY: 0.110 AC XY: 8177 AN XY: 74460

African (AFR) AF: 0.0450 AC: 1872 AN: 41570

American (AMR) AF: 0.0770 AC: 1178 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3470

East Asian (EAS) AF: 0.00751 AC: 39 AN: 5190

South Asian (SAS) AF: 0.234 AC: 1131 AN: 4830

European-Finnish (FIN) AF: 0.124 AC: 1313 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10500 AN: 68010

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.136 Hom.: 2656

Bravo AF: 0.0995

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.54
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

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: rs1868755; hg19: chr18-42637790;