rs3744825

Variant names:

• chr18-44952641-G-A
• rs3744825
• NM_015559.3:c.3301G>A

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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 1.23
• Publications: 41 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=0.004114777).
• BP6: Variant 18-44952641-G-A is Benign according to our data. Variant chr18-44952641-G-A is described in ClinVar as Benign. ClinVar VariationId is 159872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 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.3301G>A	p.Val1101Ile	missense	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.3301G>A	p.Val1101Ile	missense	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.3301G>A	p.Val1101Ile	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.3301G>A	p.Val1101Ile	missense	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000677068.1		c.3301G>A	p.Val1101Ile	missense	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
	SETBP1	ENST00000677077.1		c.3301G>A	p.Val1101Ile	missense	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

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

GnomAD2 exomes AF: 0.123 AC: 30826 AN: 250638 AF XY: 0.123

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 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

African (AFR) AF: 0.0479 AC: 1603 AN: 33478

American (AMR) AF: 0.0824 AC: 3684 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3649 AN: 26132

East Asian (EAS) AF: 0.310 AC: 12320 AN: 39694

South Asian (SAS) AF: 0.0836 AC: 7210 AN: 86256

European-Finnish (FIN) AF: 0.135 AC: 7197 AN: 53420

Middle Eastern (MID) AF: 0.0969 AC: 559 AN: 5766

European-Non Finnish (NFE) AF: 0.129 AC: 143717 AN: 1111834

Other (OTH) AF: 0.131 AC: 7905 AN: 60388

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

African (AFR) AF: 0.0503 AC: 2087 AN: 41500

American (AMR) AF: 0.0862 AC: 1317 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1443 AN: 5150

South Asian (SAS) AF: 0.0950 AC: 457 AN: 4812

European-Finnish (FIN) AF: 0.142 AC: 1494 AN: 10544

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8525 AN: 67980

Other (OTH) AF: 0.120 AC: 252 AN: 2108

Alfa AF: 0.122 Hom.: 4218

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.033
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.052	B
Vest4		0.095
MPC		0.22
ClinPred		0.0021	T
GERP RS		-0.53
Varity_R		0.027
gMVP		0.083
Mutation Taster		=100/0	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: rs3744825; hg19: chr18-42532606; COSMIC: COSV56312865;