chr18-45063305-G-T

Variant names:

• chr18-45063305-G-T
• rs117498128
• NM_015559.3:c.4398G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015559.3(SETBP1):​c.4398G>T​(p.Glu1466Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,604,890 control chromosomes in the GnomAD database, including 183 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1466K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0082 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0084 (168 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.31
• Publications: 15 publications found

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]

SETBP1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 29

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Schinzel-Giedion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• intellectual disability-expressive aphasia-facial dysmorphism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029321015).
• BP6: Variant 18-45063305-G-T is Benign according to our data. Variant chr18-45063305-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00816 (1242/152208) while in subpopulation SAS AF = 0.0404 (195/4822). AF 95% confidence interval is 0.0358. There are 15 homozygotes in GnomAd4. There are 625 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1242 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	NM_015559.3	MANE Select	c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	NP_056374.2
	SETBP1	NM_001379141.1		c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	NP_001366070.1
	SETBP1	NM_001379142.1		c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	NP_001366071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	ENSP00000497406.1
	SETBP1	ENST00000677068.1		c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	ENSP00000504398.1
	SETBP1	ENST00000677077.1		c.4398G>T	p.Glu1466Asp	missense	Exon 6 of 6	ENSP00000503656.1

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1242 AN: 152090 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0226

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.0115 AC: 2647 AN: 230286 AF XY: 0.0130

Gnomad AFR exome AF: 0.00945

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0237

Gnomad FIN exome AF: 0.00409

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00845 AC: 12270 AN: 1452682 Hom.: 168 Cov.: 33 AF XY: 0.00937 AC XY: 6764 AN XY: 721860

African (AFR) AF: 0.00960 AC: 318 AN: 33138

American (AMR) AF: 0.00658 AC: 286 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 340 AN: 25986

East Asian (EAS) AF: 0.0187 AC: 729 AN: 39088

South Asian (SAS) AF: 0.0399 AC: 3390 AN: 84920

European-Finnish (FIN) AF: 0.00408 AC: 215 AN: 52664

Middle Eastern (MID) AF: 0.0293 AC: 169 AN: 5760

European-Non Finnish (NFE) AF: 0.00552 AC: 6112 AN: 1107548

Other (OTH) AF: 0.0118 AC: 711 AN: 60086

GnomAD4 genome AF: 0.00816 AC: 1242 AN: 152208 Hom.: 15 Cov.: 31 AF XY: 0.00840 AC XY: 625 AN XY: 74424

African (AFR) AF: 0.00939 AC: 390 AN: 41524

American (AMR) AF: 0.00843 AC: 129 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3466

East Asian (EAS) AF: 0.0225 AC: 116 AN: 5166

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4822

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 68000

Other (OTH) AF: 0.0109 AC: 23 AN: 2106

Alfa AF: 0.00774 Hom.: 23

Bravo AF: 0.00910

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.0114 AC: 1387

Asia WGS AF: 0.0400 AC: 137 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27611742)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Schinzel-Giedion syndrome Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jun 12, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Schinzel-Giedion syndrome;C4015141:Intellectual disability, autosomal dominant 29 Benign:1

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.079
Sift	Benign	0.084	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.087		Loss of helix (P = 0.079)
MPC		1.2
ClinPred		0.0066	T
GERP RS		3.3
Varity_R		0.084
gMVP		0.38
Mutation Taster		=63/37	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117498128; hg19: chr18-42643270; COSMIC: COSV56314036;