rs1231303606

Variant names:

• chr18-44701385-A-AG
• rs1231303606
• NM_015559.3:c.44dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015559.3(SETBP1):​c.44dupG​(p.Glu16ArgfsTer47) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SETBP1 NM_015559.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.59
• Publications: 0 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 116 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-44701385-A-AG is Pathogenic according to our data. Variant chr18-44701385-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 934587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015559.3. 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.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 6	NP_001366071.1	Q9Y6X0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000426838.8	TSL:1	c.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 4	ENSP00000390687.3	Q9Y6X0-2
	SETBP1	ENST00000677068.1		c.44dupG	p.Glu16ArgfsTer47	frameshift	Exon 2 of 6	ENSP00000504398.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 161782 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392070 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 685118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31528

American (AMR) AF: 0.00 AC: 0 AN: 34942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24162

East Asian (EAS) AF: 0.00 AC: 0 AN: 36028

South Asian (SAS) AF: 0.00 AC: 0 AN: 77958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074542

Other (OTH) AF: 0.00 AC: 0 AN: 57448

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 29 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1231303606; hg19: chr18-42281350;