Variant 18-44701395-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015559.3(SETBP1):c.49T>C(p.Ser17Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,557,286 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SETBP1
NM_015559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.879

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13167769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3 linkuse as main transcript	c.49T>C	p.Ser17Pro	missense_variant	2/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2 linkuse as main transcript	c.49T>C	p.Ser17Pro	missense_variant	2/6		NM_015559.3	P2	Q9Y6X0-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151382

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1405904

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

693254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73856

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 22, 2023

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 17 of the SETBP1 protein (p.Ser17Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SETBP1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.65

T;.;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.55

N;N;N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.4

N;.;N;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.0090

D;.;D;.;.

Sift4G

Uncertain

0.030

D;.;D;T;.

Polyphen

0.98

D;P;P;.;.

Vest4

0.48

MutPred

0.10

Loss of phosphorylation at S17 (P = 0.0134);Loss of phosphorylation at S17 (P = 0.0134);Loss of phosphorylation at S17 (P = 0.0134);Loss of phosphorylation at S17 (P = 0.0134);Loss of phosphorylation at S17 (P = 0.0134);

MVP

0.35

MPC

0.52

ClinPred

0.45

GERP RS

4.5

Varity_R

0.24

gMVP

0.11

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