chr18-45063547-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015559.3(SETBP1):c.4640C>A(p.Thr1547Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,368,854 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1547S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 7 hom., cov: 24)

Exomes 𝑓: 0.0014 ( 54 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.34

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019431114).

BP6

Variant 18-45063547-C-A is Benign according to our data. Variant chr18-45063547-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3 link	c.4640C>A	p.Thr1547Asn	missense_variant	Exon 6 of 6	ENST00000649279.2	NP_056374.2	Q9Y6X0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2 link	c.4640C>A	p.Thr1547Asn	missense_variant	Exon 6 of 6		NM_015559.3	ENSP00000497406.1		Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

489

AN:

129802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000114

Gnomad OTH

AF:

0.00643

GnomAD2 exomes

AF:

0.0105

AC:

1134

AN:

107896

AF XY:

0.00783

show subpopulations

Gnomad AFR exome

AF:

0.000203

Gnomad AMR exome

AF:

0.0534

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.00726

GnomAD4 exome

AF:

0.00139

AC:

1717

AN:

1239008

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

707

AN XY:

610886

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

26726

American (AMR)

AF:

0.0535

AC:

1580

AN:

29534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20244

East Asian (EAS)

AF:

0.00

AC:

AN:

31172

South Asian (SAS)

AF:

0.00

AC:

AN:

67628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3488

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

964446

Other (OTH)

AF:

0.00144

AC:

AN:

50846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00379

AC:

492

AN:

129846

Hom.:

Cov.:

AF XY:

0.00425

AC XY:

265

AN XY:

62404

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

34430

American (AMR)

AF:

0.0354

AC:

417

AN:

11788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3138

East Asian (EAS)

AF:

0.00

AC:

AN:

4372

South Asian (SAS)

AF:

0.00

AC:

AN:

3934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

61346

Other (OTH)

AF:

0.00637

AC:

AN:

1728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

113

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:

0.000404

Hom.:

Bravo

AF:

0.00620

ExAC

AF:

0.00384

AC:

365

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.49

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L

PhyloP100

1.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.33

.;N

REVEL

Benign

0.068

Sift

Uncertain

0.0090

.;D

Sift4G

Uncertain

0.043

.;D

Polyphen

0.23

B;B

Vest4

0.065

MPC

1.6

ClinPred

0.027

GERP RS

4.8

Varity_R

0.16

gMVP

0.17

Mutation Taster

=87/13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over