rs587784381

chr18-44701392-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_015559.3(SETBP1):c.46G>A(p.Glu16Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,554,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.59

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16270885).
• BP6: Variant 18-44701392-G-A is Benign according to our data. Variant chr18-44701392-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3	c.46G>A	p.Glu16Lys	missense_variant	2/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.46G>A	p.Glu16Lys	missense_variant	2/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 18 AN: 172916 Hom.: 0 AF XY: 0.000130 AC XY: 12 AN XY: 92178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 161 AN: 1402496 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 77 AN XY: 691364

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: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74310

Gnomad4 AFR AF: 0.0000483

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: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000118 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SETBP1: BP4 -

Schinzel-Giedion syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 05, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;.;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.69	N;N;N;.;.
MutationTaster	Benign	0.58	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;.;N;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D;.;D;.;.
Sift4G	Uncertain	0.016	D;.;D;D;.
Polyphen		0.97	D;B;B;.;.
Vest4		0.77
MutPred		0.19		Gain of MoRF binding (P = 0.0027);Gain of MoRF binding (P = 0.0027);Gain of MoRF binding (P = 0.0027);Gain of MoRF binding (P = 0.0027);Gain of MoRF binding (P = 0.0027);
MVP		0.17
MPC		0.38
ClinPred		0.21	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.33

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: rs587784381; hg19: chr18-42281357; COSMIC: COSV56320709;