Genetic Variant SETBP1:p.Ser1275Ser (chr18-44953165-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015559.3(SETBP1):c.3825A>G(p.Ser1275Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,613,938 control chromosomes in the GnomAD database, including 609,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1275S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.90 ( 62422 hom., cov: 30)

Exomes 𝑓: 0.86 ( 546681 hom. )

Consequence

SETBP1
NM_015559.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.71

Publications

29 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 18-44953165-A-G is Benign according to our data. Variant chr18-44953165-A-G is described in ClinVar as Benign. ClinVar VariationId is 159875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.71 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.965 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	HGVSp	Effect	Exon Rank	Protein	UniProt
SETBP1	NM_015559.3	MANE Select	c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
SETBP1	NM_001379141.1		c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
SETBP1	NM_001379142.1		c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	NP_001366071.1	Q9Y6X0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETBP1	ENST00000649279.2	MANE Select	c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
SETBP1	ENST00000677068.1		c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
SETBP1	ENST00000677077.1		c.3825A>G	p.Ser1275Ser	synonymous	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.905

AC:

137483

AN:

151986

Hom.:

62365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.973

Gnomad AMI

AF:

0.893

Gnomad AMR

AF:

0.939

Gnomad ASJ

AF:

0.876

Gnomad EAS

AF:

0.957

Gnomad SAS

AF:

0.803

Gnomad FIN

AF:

0.888

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.862

Gnomad OTH

AF:

0.921

GnomAD2 exomes

AF:

0.882

AC:

220603

AN:

250116

AF XY:

0.873

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.959

Gnomad ASJ exome

AF:

0.888

Gnomad EAS exome

AF:

0.953

Gnomad FIN exome

AF:

0.879

Gnomad NFE exome

AF:

0.857

Gnomad OTH exome

AF:

0.895

GnomAD4 exome

AF:

0.864

AC:

1262703

AN:

1461834

Hom.:

546681

Cov.:

AF XY:

0.861

AC XY:

626068

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.978

AC:

32737

AN:

33478

American (AMR)

AF:

0.957

AC:

42789

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.891

AC:

23276

AN:

26136

East Asian (EAS)

AF:

0.974

AC:

38646

AN:

39694

South Asian (SAS)

AF:

0.797

AC:

68710

AN:

86258

European-Finnish (FIN)

AF:

0.872

AC:

46563

AN:

53406

Middle Eastern (MID)

AF:

0.905

AC:

5218

AN:

5768

European-Non Finnish (NFE)

AF:

0.856

AC:

951891

AN:

1111978

Other (OTH)

AF:

0.875

AC:

52873

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

11231

22462

33692

44923

56154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21206

42412

63618

84824

106030

<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:

0.905

AC:

137600

AN:

152104

Hom.:

62422

Cov.:

AF XY:

0.904

AC XY:

67229

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.973

AC:

40382

AN:

41498

American (AMR)

AF:

0.939

AC:

14358

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.876

AC:

3040

AN:

3472

East Asian (EAS)

AF:

0.957

AC:

4934

AN:

5154

South Asian (SAS)

AF:

0.803

AC:

3865

AN:

4816

European-Finnish (FIN)

AF:

0.888

AC:

9392

AN:

10576

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.862

AC:

58617

AN:

67990

Other (OTH)

AF:

0.921

AC:

1937

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

668

1335

2003

2670

3338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.883

Hom.:

96841

Bravo

AF:

0.916

Asia WGS

AF:

0.902

AC:

3135

AN:

3478

EpiCase

AF:

0.871

EpiControl

AF:

0.872

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Schinzel-Giedion syndrome (2)

Intellectual disability, autosomal dominant 29 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.010

(source)

DANN

Benign

0.35

PhyloP100

-1.7

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over