rs767301100

chr18-44953301-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_015559.3(SETBP1):c.3961C>T(p.Arg1321Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1321H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.50

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 18-44953301-C-T is Benign according to our data. Variant chr18-44953301-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 562037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETBP1	NM_015559.3	c.3961C>T	p.Arg1321Cys	missense_variant	4/6	ENST00000649279.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETBP1	ENST00000649279.2	c.3961C>T	p.Arg1321Cys	missense_variant	4/6		NM_015559.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 248970 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461694 Hom.: 0 Cov.: 36 AF XY: 0.0000275 AC XY: 20 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

Gnomad4 AFR AF: 0.0000241

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

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	Reported in a patient with mesothelioma in published literature; however, additional information was not provided (Yoshikawa et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 32206572, 28191889, 33004838) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SETBP1: BP4 -

Intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.58	T
Polyphen		1.0	D;D
Vest4		0.66
MVP		0.52
MPC		1.0
ClinPred		0.59	D
GERP RS		6.2
Varity_R		0.26
gMVP		0.47

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: rs767301100; hg19: chr18-42533266;