chr18-44680945-T-TG

Variant names:

• chr18-44680945-T-TG
• rs886053786
• NM_015559.3:c.-241dupG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_015559.3(SETBP1):​c.-241dupG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 151,204 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SETBP1 NM_015559.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.914
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 18-44680945-T-TG is Benign according to our data. Variant chr18-44680945-T-TG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 326718.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00149 (225/151204) while in subpopulation AMR AF = 0.00493 (75/15224). AF 95% confidence interval is 0.00403. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 225 AD gene.

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.-241dupG		5_prime_UTR	Exon 1 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001410862.1		c.-241dupG		5_prime_UTR	Exon 1 of 5	NP_001397791.1	A0A7I2V4X1
	SETBP1	NM_001379141.1		c.-173+558dupG		intron	N/A	NP_001366070.1	Q9Y6X0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.-241dupG		5_prime_UTR	Exon 1 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000426838.8	TSL:1	c.-173+558dupG		intron	N/A	ENSP00000390687.3	Q9Y6X0-2
	SETBP1	ENST00000677699.1		c.-241dupG		5_prime_UTR	Exon 1 of 5	ENSP00000503964.1	A0A7I2V4X1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 226 AN: 151086 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00145

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 66 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 46

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00149 AC: 225 AN: 151204 Hom.: 1 Cov.: 31 AF XY: 0.00157 AC XY: 116 AN XY: 73862

African (AFR) AF: 0.00112 AC: 46 AN: 41190

American (AMR) AF: 0.00493 AC: 75 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3462

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5152

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4762

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10390

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

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 67732

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000270 Hom.: 0

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Schinzel-Giedion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886053786; hg19: chr18-42260910; COSMIC: COSV105165199; COSMIC: COSV105165199;