chr18-44952639-A-G

Variant names:

• chr18-44952639-A-G
• rs149162154
• NM_015559.3:c.3299A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015559.3(SETBP1):​c.3299A>G​(p.His1100Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00129 in 1,613,852 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1100H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: SETBP1 NM_015559.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.97
• 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: 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 -16 ACMG points.

• BP6: Variant 18-44952639-A-G is Benign according to our data. Variant chr18-44952639-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00107 (162/152100) while in subpopulation NFE AF = 0.00179 (122/67976). AF 95% confidence interval is 0.00154. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 162 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.3299A>G	p.His1100Arg	missense	Exon 4 of 6	NP_056374.2	Q9Y6X0-1
	SETBP1	NM_001379141.1		c.3299A>G	p.His1100Arg	missense	Exon 4 of 6	NP_001366070.1	Q9Y6X0-1
	SETBP1	NM_001379142.1		c.3299A>G	p.His1100Arg	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.3299A>G	p.His1100Arg	missense	Exon 4 of 6	ENSP00000497406.1	Q9Y6X0-1
	SETBP1	ENST00000677068.1		c.3299A>G	p.His1100Arg	missense	Exon 4 of 6	ENSP00000504398.1	Q9Y6X0-1
	SETBP1	ENST00000677077.1		c.3299A>G	p.His1100Arg	missense	Exon 4 of 6	ENSP00000503656.1	Q9Y6X0-1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 162 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 286 AN: 250672 AF XY: 0.00122

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00131 AC: 1921 AN: 1461752 Hom.: 4 Cov.: 38 AF XY: 0.00140 AC XY: 1015 AN XY: 727146

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00177 AC: 153 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00149 AC: 1660 AN: 1111880

Other (OTH) AF: 0.000927 AC: 56 AN: 60394

GnomAD4 genome AF: 0.00107 AC: 162 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74342

African (AFR) AF: 0.000145 AC: 6 AN: 41514

American (AMR) AF: 0.00157 AC: 24 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4814

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00150 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00131

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.0	L
PhyloP100		6.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.95
MPC		1.0
ClinPred		0.028	T
GERP RS		5.9
Varity_R		0.54
gMVP		0.66
Mutation Taster		=86/14	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: rs149162154; hg19: chr18-42532604;