18-44876705-C-CTCTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The ENST00000426838.8(SETBP1):c.681_682insTCTT(p.Thr228SerfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,546,794 control chromosomes in the GnomAD database, including 232,434 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 21965 hom., cov: 0)

Exomes 𝑓: 0.55 ( 210469 hom. )

Consequence

SETBP1
ENST00000426838.8 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.28

Publications

28 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0645 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

BP6

Variant 18-44876705-C-CTCTT is Benign according to our data. Variant chr18-44876705-C-CTCTT is described in ClinVar as [Benign]. Clinvar id is 326725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETBP1	NM_015559.3 link	c.540+7422_540+7423insTCTT		intron_variant	Intron 3 of 5	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.540+7422_540+7423insTCTT		intron_variant	Intron 3 of 5		NM_015559.3	ENSP00000497406.1		Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.538

AC:

81389

AN:

151334

Hom.:

21949

Cov.:

show subpopulations

Gnomad AFR

AF:

0.532

Gnomad AMI

AF:

0.652

Gnomad AMR

AF:

0.498

Gnomad ASJ

AF:

0.585

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.589

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.514

GnomAD2 exomes

AF:

0.522

AC:

80825

AN:

154924

AF XY:

0.516

show subpopulations

Gnomad AFR exome

AF:

0.535

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.590

Gnomad EAS exome

AF:

0.500

Gnomad FIN exome

AF:

0.595

Gnomad NFE exome

AF:

0.550

Gnomad OTH exome

AF:

0.514

GnomAD4 exome

AF:

0.547

AC:

763310

AN:

1395344

Hom.:

210469

Cov.:

AF XY:

0.544

AC XY:

374055

AN XY:

688230

show subpopulations

African (AFR)

AF:

0.537

AC:

16893

AN:

31484

American (AMR)

AF:

0.469

AC:

16658

AN:

35516

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

14814

AN:

25068

East Asian (EAS)

AF:

0.480

AC:

17127

AN:

35710

South Asian (SAS)

AF:

0.428

AC:

33745

AN:

78898

European-Finnish (FIN)

AF:

0.590

AC:

29037

AN:

49226

Middle Eastern (MID)

AF:

0.465

AC:

2630

AN:

5656

European-Non Finnish (NFE)

AF:

0.559

AC:

601363

AN:

1075960

Other (OTH)

AF:

0.537

AC:

31043

AN:

57826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

17102

34204

51305

68407

85509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17088

34176

51264

68352

85440

<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:

0.538

AC:

81458

AN:

151450

Hom.:

21965

Cov.:

AF XY:

0.536

AC XY:

39626

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.531

AC:

21924

AN:

41252

American (AMR)

AF:

0.499

AC:

7602

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

2026

AN:

3464

East Asian (EAS)

AF:

0.481

AC:

2468

AN:

5130

South Asian (SAS)

AF:

0.416

AC:

2000

AN:

4808

European-Finnish (FIN)

AF:

0.589

AC:

6169

AN:

10472

Middle Eastern (MID)

AF:

0.534

AC:

156

AN:

292

European-Non Finnish (NFE)

AF:

0.552

AC:

37424

AN:

67774

Other (OTH)

AF:

0.520

AC:

1096

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1915

3829

5744

7658

9573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.538

Hom.:

13187

Asia WGS

AF:

0.490

AC:

1709

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 3542/6628=53.43% -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 59. Only high quality variants are reported. -

Schinzel-Giedion syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.3

Mutation Taster

=189/11

polymorphism (auto)

(source)

Splicing

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