chr18-44701183-C-G

Variant names:

• chr18-44701183-C-G
• rs145284354
• NM_015559.3:c.-164C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_015559.3(SETBP1):​c.-164C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 630,186 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: SETBP1 NM_015559.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.438
• Publications: 0 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)
• Schinzel-Giedion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• intellectual disability-expressive aphasia-facial dysmorphism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 18-44701183-C-G is Benign according to our data. Variant chr18-44701183-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2578809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00137 (208/152292) while in subpopulation AMR AF = 0.00274 (42/15304). AF 95% confidence interval is 0.00209. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 208 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.-164C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_015559.3	MANE Select	c.-164C>G		5_prime_UTR	Exon 2 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.-164C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001366070.1	Q9Y6X0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETBP1	ENST00000649279.2	MANE Select	c.-164C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000426838.8	TSL:1	c.-164C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000390687.3	Q9Y6X0-2
	SETBP1	ENST00000649279.2	MANE Select	c.-164C>G		5_prime_UTR	Exon 2 of 6	ENSP00000497406.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00164 AC: 785 AN: 477894 Hom.: 2 Cov.: 7 AF XY: 0.00172 AC XY: 414 AN XY: 241320

African (AFR) AF: 0.000993 AC: 13 AN: 13086

American (AMR) AF: 0.00236 AC: 31 AN: 13138

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 285 AN: 12424

East Asian (EAS) AF: 0.00 AC: 0 AN: 29200

South Asian (SAS) AF: 0.000570 AC: 12 AN: 21040

European-Finnish (FIN) AF: 0.0000321 AC: 1 AN: 31176

Middle Eastern (MID) AF: 0.0131 AC: 26 AN: 1978

European-Non Finnish (NFE) AF: 0.000988 AC: 326 AN: 329962

Other (OTH) AF: 0.00351 AC: 91 AN: 25890

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74456

African (AFR) AF: 0.000385 AC: 16 AN: 41550

American (AMR) AF: 0.00274 AC: 42 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.00161

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		0.44
PromoterAI		-0.016	Neutral
Mutation Taster		=294/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs145284354; hg19: chr18-42281148;