chr18-44953350-T-A

Variant names:

• chr18-44953350-T-A
• rs3786177
• NM_015559.3:c.4000+10T>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.4000+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,609,664 control chromosomes in the GnomAD database, including 12,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1047 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11890 hom.)
• Consequence: SETBP1 NM_015559.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.586
• Publications: 12 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 18-44953350-T-A is Benign according to our data. Variant chr18-44953350-T-A is described in ClinVar as Benign. ClinVar VariationId is 159877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 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.4000+10T>A		intron	N/A	NP_056374.2
	SETBP1	NM_001379141.1		c.4000+10T>A		intron	N/A	NP_001366070.1
	SETBP1	NM_001379142.1		c.4000+10T>A		intron	N/A	NP_001366071.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.4000+10T>A		intron	N/A	ENSP00000497406.1
	SETBP1	ENST00000677068.1		c.4000+10T>A		intron	N/A	ENSP00000504398.1
	SETBP1	ENST00000677077.1		c.4000+10T>A		intron	N/A	ENSP00000503656.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15757 AN: 152076 Hom.: 1034 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.139 AC: 34156 AN: 245482 AF XY: 0.134

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.0770

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.120 AC: 174169 AN: 1457470 Hom.: 11890 Cov.: 33 AF XY: 0.119 AC XY: 86625 AN XY: 725188

African (AFR) AF: 0.0373 AC: 1247 AN: 33416

American (AMR) AF: 0.301 AC: 13408 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3113 AN: 26112

East Asian (EAS) AF: 0.191 AC: 7567 AN: 39676

South Asian (SAS) AF: 0.121 AC: 10441 AN: 86042

European-Finnish (FIN) AF: 0.0745 AC: 3932 AN: 52806

Middle Eastern (MID) AF: 0.133 AC: 765 AN: 5764

European-Non Finnish (NFE) AF: 0.114 AC: 126562 AN: 1108892

Other (OTH) AF: 0.118 AC: 7134 AN: 60242

GnomAD4 genome AF: 0.104 AC: 15795 AN: 152194 Hom.: 1047 Cov.: 32 AF XY: 0.106 AC XY: 7886 AN XY: 74418

African (AFR) AF: 0.0418 AC: 1738 AN: 41554

American (AMR) AF: 0.215 AC: 3281 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3472

East Asian (EAS) AF: 0.181 AC: 933 AN: 5154

South Asian (SAS) AF: 0.114 AC: 552 AN: 4824

European-Finnish (FIN) AF: 0.0835 AC: 885 AN: 10604

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

European-Non Finnish (NFE) AF: 0.112 AC: 7621 AN: 67984

Other (OTH) AF: 0.118 AC: 250 AN: 2110

Alfa AF: 0.0706 Hom.: 102

Bravo AF: 0.114

Asia WGS AF: 0.182 AC: 634 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Schinzel-Giedion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		-0.59
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: rs3786177; hg19: chr18-42533315; COSMIC: COSV56314030;