chr18-45063305-G-T

Position:

chr18-45063305-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015559.3(SETBP1):c.4398G>T(p.Glu1466Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,604,890 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 15 hom., cov: 31)

Exomes 𝑓: 0.0084 ( 168 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029321015).

BP6

Variant 18-45063305-G-T is Benign according to our data. Variant chr18-45063305-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 159880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00816 (1242/152208) while in subpopulation SAS AF= 0.0404 (195/4822). AF 95% confidence interval is 0.0358. There are 15 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETBP1	NM_015559.3 linkuse as main transcript	c.4398G>T	p.Glu1466Asp	missense_variant	6/6	ENST00000649279.2	NP_056374.2	Q9Y6X0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2 linkuse as main transcript	c.4398G>T	p.Glu1466Asp	missense_variant	6/6		NM_015559.3	ENSP00000497406.1		Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1242

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00844

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.0226

Gnomad SAS

AF:

0.0404

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.0106

GnomAD3 exomes

AF:

0.0115

AC:

2647

AN:

230286

Hom.:

AF XY:

0.0130

AC XY:

1613

AN XY:

124550

show subpopulations

Gnomad AFR exome

AF:

0.00945

Gnomad AMR exome

AF:

0.00651

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0237

Gnomad SAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.00409

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00845

AC:

12270

AN:

1452682

Hom.:

168

Cov.:

AF XY:

0.00937

AC XY:

6764

AN XY:

721860

show subpopulations

Gnomad4 AFR exome

AF:

0.00960

Gnomad4 AMR exome

AF:

0.00658

Gnomad4 ASJ exome

AF:

0.0131

Gnomad4 EAS exome

AF:

0.0187

Gnomad4 SAS exome

AF:

0.0399

Gnomad4 FIN exome

AF:

0.00408

Gnomad4 NFE exome

AF:

0.00552

Gnomad4 OTH exome

AF:

0.0118

GnomAD4 genome

AF:

0.00816

AC:

1242

AN:

152208

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

625

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00939

Gnomad4 AMR

AF:

0.00843

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.0225

Gnomad4 SAS

AF:

0.0404

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00444

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00740

Hom.:

Bravo

AF:

0.00910

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.0114

AC:

1387

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	This variant is associated with the following publications: (PMID: 27611742) -

Schinzel-Giedion syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.55

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.52

.;N

REVEL

Benign

0.079

Sift

Benign

0.084

.;T

Sift4G

Benign

0.10

.;T

Polyphen

0.0

B;B

Vest4

0.036

MutPred

0.087

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MPC

1.2

ClinPred

0.0066

GERP RS

3.3

Varity_R

0.084

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over