Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015559.3(SETBP1):c.4554G>A(p.Glu1518Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000583 in 1,473,276 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00056 ( 5 hom. )

Consequence

SETBP1
NM_015559.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.80

Publications

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

SETBP1 links:

ENSG00000267101 (HGNC:):

ENSG00000267101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 18-45063461-G-A is Benign according to our data. Variant chr18-45063461-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159881.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000746 (113/151568) while in subpopulation AMR AF = 0.00105 (16/15244). AF 95% confidence interval is 0.000658. There are 1 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 113 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETBP1	NM_015559.3	MANE Select	c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	NP_056374.2
SETBP1	NM_001379141.1		c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	NP_001366070.1
SETBP1	NM_001379142.1		c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	NP_001366071.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETBP1	ENST00000649279.2	MANE Select	c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	ENSP00000497406.1
SETBP1	ENST00000677068.1		c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	ENSP00000504398.1
SETBP1	ENST00000677077.1		c.4554G>A	p.Glu1518Glu	synonymous	Exon 6 of 6	ENSP00000503656.1

Frequencies

GnomAD3 genomes

AF:

0.000746

AC:

113

AN:

151460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.000457

Gnomad OTH

AF:

0.00480

GnomAD2 exomes

AF:

0.00122

AC:

AN:

73190

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000779

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.000564

AC:

746

AN:

1321708

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

381

AN XY:

645256

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

28714

American (AMR)

AF:

0.00140

AC:

AN:

23562

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

302

AN:

19862

East Asian (EAS)

AF:

0.00

AC:

AN:

35130

South Asian (SAS)

AF:

0.000168

AC:

AN:

65568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43122

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

3822

European-Non Finnish (NFE)

AF:

0.000221

AC:

232

AN:

1047416

Other (OTH)

AF:

0.00222

AC:

121

AN:

54512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000746

AC:

113

AN:

151568

Hom.:

Cov.:

AF XY:

0.000810

AC XY:

AN XY:

74068

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41336

American (AMR)

AF:

0.00105

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.000419

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000457

AC:

AN:

67778

Other (OTH)

AF:

0.00475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00166

Hom.:

Bravo

AF:

0.000756

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (1)

Schinzel-Giedion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.0

(source)

DANN

Benign

0.62

PhyloP100

3.8

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over