ENST00000426838.8:c.681_682insTCTT

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

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
SETBP1NM_015559.3 linkc.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
SETBP1ENST00000649279.2 linkc.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.:
0
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.:
32
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
0
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
0
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.:
0
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
0
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
0
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)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs3085861; hg19: chr18-42456670; COSMIC: COSV56311994; COSMIC: COSV56311994; API