rs3744824

Variant names:

• chr18-44951272-C-T
• rs3744824
• NM_015559.3:c.1932C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-44951272-C-T
• chr18-44951272-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015559.3(SETBP1):​c.1932C>T​(p.Ser644Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,613,612 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: SETBP1 NM_015559.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.17
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 18-44951272-C-T is Benign according to our data. Variant chr18-44951272-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159870.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000887 (135/152146) while in subpopulation EAS AF = 0.0259 (134/5176). AF 95% confidence interval is 0.0223. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 135 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	NM_015559.3	MANE Select	c.1932C>T	p.Ser644Ser	synonymous	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.1932C>T	p.Ser644Ser	synonymous	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.1932C>T	p.Ser644Ser	synonymous	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.1932C>T	p.Ser644Ser	synonymous	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000677068.1		c.1932C>T	p.Ser644Ser	synonymous	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
	SETBP1	ENST00000677077.1		c.1932C>T	p.Ser644Ser	synonymous	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.000914 AC: 139 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00207 AC: 508 AN: 245934 AF XY: 0.00198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1461466 Hom.: 12 Cov.: 38 AF XY: 0.000634 AC XY: 461 AN XY: 727018

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0219 AC: 870 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112008

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152146 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0259 AC: 134 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000124 Hom.: 1

Bravo AF: 0.000994

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.3
DANN	Benign	0.83
PhyloP100		-1.2
Mutation Taster		=99/1	polymorphism

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: rs3744824; hg19: chr18-42531237;