chr18-44701395-T-C

Variant names:

• chr18-44701395-T-C
• rs1436724007
• NM_015559.3:c.49T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.879

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]

ACMG classification

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 rank	MANE	Protein	UniProt
SETBP1	NM_015559.3	c.49T>C	p.Ser17Pro	missense_variant	Exon 2 of 6	ENST00000649279.2	NP_056374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETBP1	ENST00000649279.2	c.49T>C	p.Ser17Pro	missense_variant	Exon 2 of 6		NM_015559.3	ENSP00000497406.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151382 Hom.: 0 Cov.: 32

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: 2 AN: 1405904 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 693254

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: 1 AN: 151382 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73856

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals affected with SETBP1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.65	T;.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	N;N;N;.;.
PrimateAI	Benign	0.48	T
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	T
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

Other links and lift over

dbSNP: rs1436724007; hg19: chr18-42281360;