rs1064204

Variant names:

• chr18-44952728-C-A
• rs1064204
• NM_015559.3:c.3388C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-44952728-C-A
• chr18-44952728-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015559.3(SETBP1):​c.3388C>A​(p.Pro1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,980 control chromosomes in the GnomAD database, including 12,930 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1130I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (1041 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11889 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.01
• Publications: 32 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Schinzel-Giedion syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017183125).
• BP6: Variant 18-44952728-C-A is Benign according to our data. Variant chr18-44952728-C-A is described in ClinVar as Benign. ClinVar VariationId is 159873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	NM_015559.3	MANE Select	c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	NP_001366071.1	Q9Y6X0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000677068.1		c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
	SETBP1	ENST00000677077.1		c.3388C>A	p.Pro1130Thr	missense	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15650 AN: 151996 Hom.: 1028 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0825

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.138 AC: 34749 AN: 251312 AF XY: 0.133

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.119 AC: 174179 AN: 1461866 Hom.: 11889 Cov.: 63 AF XY: 0.119 AC XY: 86575 AN XY: 727230

African (AFR) AF: 0.0359 AC: 1202 AN: 33480

American (AMR) AF: 0.301 AC: 13459 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3115 AN: 26136

East Asian (EAS) AF: 0.191 AC: 7568 AN: 39696

South Asian (SAS) AF: 0.121 AC: 10424 AN: 86258

European-Finnish (FIN) AF: 0.0739 AC: 3949 AN: 53420

Middle Eastern (MID) AF: 0.133 AC: 765 AN: 5768

European-Non Finnish (NFE) AF: 0.114 AC: 126566 AN: 1111988

Other (OTH) AF: 0.118 AC: 7131 AN: 60396

GnomAD4 genome AF: 0.103 AC: 15687 AN: 152114 Hom.: 1041 Cov.: 32 AF XY: 0.105 AC XY: 7829 AN XY: 74338

African (AFR) AF: 0.0402 AC: 1670 AN: 41528

American (AMR) AF: 0.214 AC: 3266 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3466

East Asian (EAS) AF: 0.183 AC: 944 AN: 5158

South Asian (SAS) AF: 0.114 AC: 549 AN: 4800

European-Finnish (FIN) AF: 0.0825 AC: 874 AN: 10590

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7604 AN: 68002

Other (OTH) AF: 0.118 AC: 249 AN: 2108

Alfa AF: 0.114 Hom.: 4365

Bravo AF: 0.113

TwinsUK AF: 0.112 AC: 414

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.120 AC: 1030

ExAC AF: 0.129 AC: 15657

Asia WGS AF: 0.181 AC: 629 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.116

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Schinzel-Giedion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.049
Sift	Benign	0.10	T
Sift4G	Benign	0.079	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.32
ClinPred		0.0095	T
GERP RS		4.1
Varity_R		0.088
gMVP		0.33
Mutation Taster		=99/1	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: rs1064204; hg19: chr18-42532693; COSMIC: COSV56312562;