18-44680945-T-TG

Position:

• chr18-44680945-T-TG

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 326718.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.-241dupG		5_prime_UTR_variant	1/6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279	c.-241dupG		5_prime_UTR_variant	1/6		NM_015559.3	ENSP00000497406.1
SETBP1	ENST00000426838.8	c.-173+558dupG		intron_variant		1		ENSP00000390687.3
SETBP1	ENST00000677699	c.-241dupG		5_prime_UTR_variant	1/5			ENSP00000503964.1
SETBP1	ENST00000677068.1	c.-173+558dupG		intron_variant				ENSP00000504398.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00112

Gnomad4 AMR AF: 0.00493

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00144

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Schinzel-Giedion syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

SETBP1: BS1 -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs886053786; hg19: chr18-42260910;