rs201973930

Variant names:

• chr18-45063547-C-A
• rs201973930
• NM_015559.3:c.4640C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-45063547-C-A
• chr18-45063547-C-G
• chr18-45063547-C-T

Variant summary

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

The ENST00000649279.2(SETBP1):​c.4640C>A​(p.Thr1547Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,368,854 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1547S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 24)
  • Exomes 𝑓: 0.0014 (54 hom.)
• Consequence: SETBP1 ENST00000649279.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.34
• 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: 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

ENSG00000267101 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019431114).
• BP6: Variant 18-45063547-C-A is Benign according to our data. Variant chr18-45063547-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649279.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	NM_015559.3	MANE Select	c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	NP_056374.2
	SETBP1	NM_001379141.1		c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	NP_001366070.1
	SETBP1	NM_001379142.1		c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	NP_001366071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	ENSP00000497406.1
	SETBP1	ENST00000677068.1		c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	ENSP00000504398.1
	SETBP1	ENST00000677077.1		c.4640C>A	p.Thr1547Asn	missense	Exon 6 of 6	ENSP00000503656.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 489 AN: 129802 Hom.: 7 Cov.: 24

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.00643

GnomAD2 exomes AF: 0.0105 AC: 1134 AN: 107896 AF XY: 0.00783

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.00726

GnomAD4 exome AF: 0.00139 AC: 1717 AN: 1239008 Hom.: 54 Cov.: 23 AF XY: 0.00116 AC XY: 707 AN XY: 610886

African (AFR) AF: 0.000674 AC: 18 AN: 26726

American (AMR) AF: 0.0535 AC: 1580 AN: 29534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20244

East Asian (EAS) AF: 0.00 AC: 0 AN: 31172

South Asian (SAS) AF: 0.00 AC: 0 AN: 67628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3488

European-Non Finnish (NFE) AF: 0.0000477 AC: 46 AN: 964446

Other (OTH) AF: 0.00144 AC: 73 AN: 50846

GnomAD4 genome AF: 0.00379 AC: 492 AN: 129846 Hom.: 7 Cov.: 24 AF XY: 0.00425 AC XY: 265 AN XY: 62404

African (AFR) AF: 0.00166 AC: 57 AN: 34430

American (AMR) AF: 0.0354 AC: 417 AN: 11788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3138

East Asian (EAS) AF: 0.00 AC: 0 AN: 4372

South Asian (SAS) AF: 0.00 AC: 0 AN: 3934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.000114 AC: 7 AN: 61346

Other (OTH) AF: 0.00637 AC: 11 AN: 1728

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.00620

ExAC AF: 0.00384 AC: 365

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.068
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.043	D
Polyphen		0.23	B
Vest4		0.065
MPC		1.6
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.17
Mutation Taster		=87/13	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: rs201973930; hg19: chr18-42643512;