18-44950031-G-C

Variant names:

• chr18-44950031-G-C
• rs11082414
• NM_015559.3:c.691G>C

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.691G>C​(p.Val231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,614,022 control chromosomes in the GnomAD database, including 33,960 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. V231I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2738 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31222 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440
• 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=0.0025821924).
• BP6: Variant 18-44950031-G-C is Benign according to our data. Variant chr18-44950031-G-C is described in ClinVar as Benign. ClinVar VariationId is 159885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.238 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.691G>C	p.Val231Leu	missense	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.691G>C	p.Val231Leu	missense	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.691G>C	p.Val231Leu	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.691G>C	p.Val231Leu	missense	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000677068.1		c.691G>C	p.Val231Leu	missense	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
	SETBP1	ENST00000677077.1		c.691G>C	p.Val231Leu	missense	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28410 AN: 152094 Hom.: 2739 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.191 AC: 47951 AN: 250928 AF XY: 0.197

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0120

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.203 AC: 296307 AN: 1461810 Hom.: 31222 Cov.: 41 AF XY: 0.204 AC XY: 148357 AN XY: 727206

African (AFR) AF: 0.154 AC: 5161 AN: 33480

American (AMR) AF: 0.179 AC: 8024 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4288 AN: 26136

East Asian (EAS) AF: 0.0163 AC: 649 AN: 39698

South Asian (SAS) AF: 0.256 AC: 22082 AN: 86258

European-Finnish (FIN) AF: 0.215 AC: 11491 AN: 53376

Middle Eastern (MID) AF: 0.234 AC: 1350 AN: 5768

European-Non Finnish (NFE) AF: 0.208 AC: 231572 AN: 1111976

Other (OTH) AF: 0.194 AC: 11690 AN: 60394

GnomAD4 genome AF: 0.187 AC: 28413 AN: 152212 Hom.: 2738 Cov.: 32 AF XY: 0.187 AC XY: 13919 AN XY: 74418

African (AFR) AF: 0.159 AC: 6598 AN: 41532

American (AMR) AF: 0.197 AC: 3009 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3472

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5182

South Asian (SAS) AF: 0.250 AC: 1202 AN: 4812

European-Finnish (FIN) AF: 0.205 AC: 2171 AN: 10606

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14152 AN: 68000

Other (OTH) AF: 0.202 AC: 428 AN: 2114

Alfa AF: 0.178 Hom.: 1659

Bravo AF: 0.182

TwinsUK AF: 0.207 AC: 769

ALSPAC AF: 0.199 AC: 766

ESP6500AA AF: 0.148 AC: 652

ESP6500EA AF: 0.204 AC: 1758

ExAC AF: 0.193 AC: 23408

Asia WGS AF: 0.148 AC: 518 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Schinzel-Giedion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.3
DANN	Benign	0.77
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.044
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.036
Sift	Uncertain	0.029	D
Sift4G	Benign	0.45	T
Polyphen		0.0060	B
Vest4		0.027
MPC		0.25
ClinPred		0.0025	T
GERP RS		-5.5
Varity_R		0.076
gMVP		0.13
Mutation Taster		=98/2	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: rs11082414; hg19: chr18-42529996; COSMIC: COSV56313278;