chr18-44905559-A-C

Variant names:

• chr18-44905559-A-C
• rs616444
• NM_015559.3:c.540+36276A>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+36276A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 143,912 control chromosomes in the GnomAD database, including 517 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 0.077 (517 hom., cov: 32)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.595
• Publications: 4 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.540+36276A>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+36276A>C		intron_variant	Intron 3 of 5		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11139 AN: 143792 Hom.: 516 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.0906

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0745

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

GnomAD4 genome AF: 0.0775 AC: 11150 AN: 143912 Hom.: 517 Cov.: 32 AF XY: 0.0773 AC XY: 5430 AN XY: 70282

African (AFR) AF: 0.0212 AC: 811 AN: 38200

American (AMR) AF: 0.0533 AC: 773 AN: 14506

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 476 AN: 3394

East Asian (EAS) AF: 0.0176 AC: 89 AN: 5050

South Asian (SAS) AF: 0.125 AC: 547 AN: 4376

European-Finnish (FIN) AF: 0.0935 AC: 942 AN: 10076

Middle Eastern (MID) AF: 0.0912 AC: 25 AN: 274

European-Non Finnish (NFE) AF: 0.111 AC: 7244 AN: 65154

Other (OTH) AF: 0.0792 AC: 157 AN: 1982

Alfa AF: 0.0925 Hom.: 1432

Bravo AF: 0.0665

Asia WGS AF: 0.0750 AC: 263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.49
PhyloP100		0.59
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: rs616444; hg19: chr18-42485524;