rs7228266

Variant names:

• chr18-45040568-G-A
• rs7228266
• NM_015559.3:c.4171+1913G>A

Variant summary

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

The NM_015559.3(SETBP1):​c.4171+1913G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,048 control chromosomes in the GnomAD database, including 6,880 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 0.30 (6880 hom., cov: 32)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 3 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=-0.5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.4171+1913G>A		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.4171+1913G>A		intron_variant	Intron 5 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45396 AN: 151930 Hom.: 6880 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.299 AC: 45411 AN: 152048 Hom.: 6880 Cov.: 32 AF XY: 0.294 AC XY: 21882 AN XY: 74342

African (AFR) AF: 0.274 AC: 11367 AN: 41466

American (AMR) AF: 0.299 AC: 4566 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3472

East Asian (EAS) AF: 0.269 AC: 1391 AN: 5166

South Asian (SAS) AF: 0.288 AC: 1384 AN: 4810

European-Finnish (FIN) AF: 0.257 AC: 2712 AN: 10564

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22007 AN: 67972

Other (OTH) AF: 0.308 AC: 650 AN: 2112

Alfa AF: 0.322 Hom.: 25341

Bravo AF: 0.306

Asia WGS AF: 0.294 AC: 1024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.54
PhyloP100		1.3
Mutation Taster		=99/1	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: rs7228266; hg19: chr18-42620533;