NM_015559.3:c.540+5440T>C

Variant names:

• chr18-44874723-T-C
• rs639964
• NM_015559.3:c.540+5440T>C

Variant summary

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

The NM_015559.3(SETBP1):​c.540+5440T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,978 control chromosomes in the GnomAD database, including 22,831 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 0.55 (22831 hom., cov: 31)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 7 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.540+5440T>C		intron_variant	Intron 3 of 5	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.540+5440T>C		intron_variant	Intron 3 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83051 AN: 151862 Hom.: 22809 Cov.: 31

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.523

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

GnomAD4 genome AF: 0.547 AC: 83130 AN: 151978 Hom.: 22831 Cov.: 31 AF XY: 0.545 AC XY: 40510 AN XY: 74276

African (AFR) AF: 0.546 AC: 22616 AN: 41406

American (AMR) AF: 0.502 AC: 7668 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2029 AN: 3462

East Asian (EAS) AF: 0.484 AC: 2504 AN: 5170

South Asian (SAS) AF: 0.418 AC: 2015 AN: 4816

European-Finnish (FIN) AF: 0.597 AC: 6314 AN: 10580

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.561 AC: 38112 AN: 67960

Other (OTH) AF: 0.529 AC: 1116 AN: 2110

Alfa AF: 0.528 Hom.: 9791

Bravo AF: 0.543

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.46
DANN	Benign	0.47
PhyloP100		-1.2
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: rs639964; hg19: chr18-42454688;