Genetic Variant SETBP1:c.540+36276A>C (chr18-44905559-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.595

Publications

4 publications found

Variant links:

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

SETBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SETBP1	NM_015559.3	MANE Select	c.540+36276A>C	intron	N/A	NP_056374.2	Q9Y6X0-1
SETBP1	NM_001379141.1		c.540+36276A>C	intron	N/A	NP_001366070.1	Q9Y6X0-1
SETBP1	NM_001379142.1		c.540+36276A>C	intron	N/A	NP_001366071.1	Q9Y6X0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SETBP1	ENST00000649279.2	MANE Select	c.540+36276A>C	intron	N/A	ENSP00000497406.1	Q9Y6X0-1
SETBP1	ENST00000677068.1		c.540+36276A>C	intron	N/A	ENSP00000504398.1	Q9Y6X0-1
SETBP1	ENST00000677077.1		c.540+36276A>C	intron	N/A	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.0775

AC:

11139

AN:

143792

Hom.:

516

Cov.:

show subpopulations

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.:

AF XY:

0.0773

AC XY:

5430

AN XY:

70282

show subpopulations

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:

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:

AN:

274

European-Non Finnish (NFE)

AF:

0.111

AC:

7244

AN:

65154

Other (OTH)

AF:

0.0792

AC:

157

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

518

1036

1553

2071

2589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.4

(source)

DANN

Benign

0.49

PhyloP100

0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over