rs3744825

chr18-44952641-G-A

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.3301G>A(p.Val1101Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,728 control chromosomes in the GnomAD database, including 14,285 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1124 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13161 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.23

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=0.004114777).
• BP6: Variant 18-44952641-G-A is Benign according to our data. Variant chr18-44952641-G-A is described in ClinVar as [Benign]. Clinvar id is 159872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-44952641-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3	c.3301G>A	p.Val1101Ile	missense_variant	4/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.3301G>A	p.Val1101Ile	missense_variant	4/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16311 AN: 151918 Hom.: 1125 Cov.: 32

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.0949

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.123 AC: 30826 AN: 250638 Hom.: 2260 AF XY: 0.123 AC XY: 16603 AN XY: 135400

Gnomad AFR exome AF: 0.0502

Gnomad AMR exome AF: 0.0822

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.281

Gnomad SAS exome AF: 0.0838

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.129 AC: 187844 AN: 1461690 Hom.: 13161 Cov.: 49 AF XY: 0.127 AC XY: 92524 AN XY: 727100

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.0824

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.0836

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.107 AC: 16305 AN: 152038 Hom.: 1124 Cov.: 32 AF XY: 0.108 AC XY: 8006 AN XY: 74282

Gnomad4 AFR AF: 0.0503

Gnomad4 AMR AF: 0.0862

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.0950

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.120

Alfa AF: 0.126 Hom.: 3216

Bravo AF: 0.104

TwinsUK AF: 0.127 AC: 470

ALSPAC AF: 0.139 AC: 536

ESP6500AA AF: 0.0572 AC: 252

ESP6500EA AF: 0.125 AC: 1072

ExAC AF: 0.121 AC: 14714

Asia WGS AF: 0.176 AC: 610 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Schinzel-Giedion syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	10
Dann	Benign	0.87
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.46	N
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
Polyphen		0.052	B;B
Vest4		0.095
MPC		0.22
ClinPred		0.0021	T
GERP RS		-0.53
Varity_R		0.027
gMVP		0.083

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: rs3744825; hg19: chr18-42532606; COSMIC: COSV56312865;