NM_015559.3:c.540+3799A>G

Variant names:

• chr18-44873082-A-G
• rs617459
• NM_015559.3:c.540+3799A>G

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+3799A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 152,104 control chromosomes in the GnomAD database, including 22,955 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 (22955 hom., cov: 33)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 11 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=-0.92).
• 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+3799A>G		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+3799A>G		intron_variant	Intron 3 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83313 AN: 151986 Hom.: 22932 Cov.: 33

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.548 AC: 83395 AN: 152104 Hom.: 22955 Cov.: 33 AF XY: 0.547 AC XY: 40641 AN XY: 74362

African (AFR) AF: 0.551 AC: 22861 AN: 41480

American (AMR) AF: 0.502 AC: 7679 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2030 AN: 3468

East Asian (EAS) AF: 0.482 AC: 2491 AN: 5172

South Asian (SAS) AF: 0.422 AC: 2032 AN: 4816

European-Finnish (FIN) AF: 0.597 AC: 6320 AN: 10580

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38117 AN: 67988

Other (OTH) AF: 0.528 AC: 1112 AN: 2108

Alfa AF: 0.553 Hom.: 74654

Bravo AF: 0.545

Asia WGS AF: 0.492 AC: 1715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.68
DANN	Benign	0.61
PhyloP100		-0.23
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: rs617459; hg19: chr18-42453047;