rs200931857

Variant names:

• chr18-44701044-TA-T
• rs200931857
• NM_015559.3:c.-172-130delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001379142.1(SETBP1):​c.-173+4delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 287,316 control chromosomes in the GnomAD database, including 38 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (20 hom.)
• Consequence: SETBP1 NM_001379142.1 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.589
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• Schinzel-Giedion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• intellectual disability-expressive aphasia-facial dysmorphism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-44701044-TA-T is Benign according to our data. Variant chr18-44701044-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1207198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2023/152300) while in subpopulation NFE AF = 0.0192 (1303/68022). AF 95% confidence interval is 0.0183. There are 18 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2023 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379142.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	NM_015559.3	MANE Select	c.-172-130delA		intron	N/A	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.-172-130delA		intron	N/A	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.-173+4delA		splice_region intron	N/A	NP_001366071.1	Q9Y6X0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.-172-130delA		intron	N/A	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000426838.8	TSL:1	c.-172-130delA		intron	N/A	ENSP00000390687.3	Q9Y6X0-2
	SETBP1	ENST00000677068.1		c.-172-130delA		intron	N/A	ENSP00000504398.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2023 AN: 152182 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0147 AC: 1986 AN: 135016 Hom.: 20 AF XY: 0.0148 AC XY: 1008 AN XY: 68076

African (AFR) AF: 0.00305 AC: 14 AN: 4584

American (AMR) AF: 0.00504 AC: 32 AN: 6348

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 44 AN: 5062

East Asian (EAS) AF: 0.00 AC: 0 AN: 11754

South Asian (SAS) AF: 0.00758 AC: 27 AN: 3560

European-Finnish (FIN) AF: 0.0253 AC: 202 AN: 7992

Middle Eastern (MID) AF: 0.00423 AC: 3 AN: 710

European-Non Finnish (NFE) AF: 0.0181 AC: 1559 AN: 85900

Other (OTH) AF: 0.0115 AC: 105 AN: 9106

GnomAD4 genome AF: 0.0133 AC: 2023 AN: 152300 Hom.: 18 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74482

African (AFR) AF: 0.00358 AC: 149 AN: 41564

American (AMR) AF: 0.00883 AC: 135 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4824

European-Finnish (FIN) AF: 0.0322 AC: 342 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 68022

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00802 Hom.: 3

Bravo AF: 0.0108

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs200931857; hg19: chr18-42281009;