rs201973930

chr18-45063547-C-Achr18-45063547-C-Gchr18-45063547-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015559.3(SETBP1):c.4640C>A(p.Thr1547Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,368,854 control chromosomes in the GnomAD database, including 61 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1547S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 24)
  • Exomes 𝑓: 0.0014 (54 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019431114).
• BP6: Variant 18-45063547-C-A is Benign according to our data. Variant chr18-45063547-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 159882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3	c.4640C>A	p.Thr1547Asn	missense_variant	6/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.4640C>A	p.Thr1547Asn	missense_variant	6/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 489 AN: 129802 Hom.: 7 Cov.: 24

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

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: 0.000114

Gnomad OTH AF: 0.00643

GnomAD3 exomes AF: 0.0105 AC: 1134 AN: 107896 Hom.: 39 AF XY: 0.00783 AC XY: 448 AN XY: 57184

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.00139 AC: 1717 AN: 1239008 Hom.: 54 Cov.: 23 AF XY: 0.00116 AC XY: 707 AN XY: 610886

Gnomad4 AFR exome AF: 0.000674

Gnomad4 AMR exome AF: 0.0535

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00379 AC: 492 AN: 129846 Hom.: 7 Cov.: 24 AF XY: 0.00425 AC XY: 265 AN XY: 62404

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000114

Gnomad4 OTH AF: 0.00637

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.00620

ExAC AF: 0.00384 AC: 365

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 28, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.50	N
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.61	N
PrimateAI	Pathogenic	0.88	D
Polyphen		0.23	B;B
Vest4		0.065
MPC		1.6
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.17

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: rs201973930; hg19: chr18-42643512;