rs3832728

Variant names:

• chr11-47358725-GCACA-G
• rs3832728
• ENST00000533968.1:c.608_611delTGTG

Your query was ambiguous. Multiple possible variants found:

• chr11-47358725-GCACA-G
• chr11-47358725-GCACA-GCA
• chr11-47358725-GCACA-GCACACA
• chr11-47358725-GCACA-GCACACACA
• chr11-47358725-GCACA-GCACACACACA
• chr11-47358725-GCACA-GCACACACACACACACTGGCAAACATTCACA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BS1 BS2

The ENST00000533968.1(SPI1):​c.608_611delTGTG​(p.Val203AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 943,384 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 27)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: SPI1 ENST00000533968.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 0 publications found

Genes affected

SPI1 (HGNC:11241): (Spi-1 proto-oncogene) This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development. The nuclear protein binds to a purine-rich sequence known as the PU-box found near the promoters of target genes, and regulates their expression in coordination with other transcription factors and cofactors. The protein can also regulate alternative splicing of target genes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SPI1 Gene-Disease associations (from GenCC):

• agammaglobulinemia 10, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.176 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00161 (243/151014) while in subpopulation AFR AF = 0.00557 (229/41142). AF 95% confidence interval is 0.00497. There are 1 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 243 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000533968.1. 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
	SPI1	NM_003120.3	MANE Select	c.493+115_493+118delTGTG		intron	N/A	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.496+115_496+118delTGTG		intron	N/A	NP_001074016.1	P17947-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPI1	ENST00000533968.1	TSL:1	c.608_611delTGTG	p.Val203AlafsTer24	frameshift	Exon 4 of 4	ENSP00000438846.1	F5H3K6
	SPI1	ENST00000378538.8	TSL:1 MANE Select	c.493+115_493+118delTGTG		intron	N/A	ENSP00000367799.4	P17947-1
	SPI1	ENST00000227163.8	TSL:2	c.496+115_496+118delTGTG		intron	N/A	ENSP00000227163.4	P17947-2

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 241 AN: 150902 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

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: 0.0000443

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000477 AC: 58 AN: 121646 AF XY: 0.000350

Gnomad AFR exome AF: 0.00756

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000655

Gnomad OTH exome AF: 0.000270

GnomAD4 exome AF: 0.000235 AC: 186 AN: 792370 Hom.: 0 AF XY: 0.000170 AC XY: 70 AN XY: 411674

African (AFR) AF: 0.00634 AC: 125 AN: 19712

American (AMR) AF: 0.000322 AC: 11 AN: 34154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21048

East Asian (EAS) AF: 0.00 AC: 0 AN: 32076

South Asian (SAS) AF: 0.00 AC: 0 AN: 66384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4542

European-Non Finnish (NFE) AF: 0.0000720 AC: 39 AN: 541476

Other (OTH) AF: 0.000289 AC: 11 AN: 38040

GnomAD4 genome AF: 0.00161 AC: 243 AN: 151014 Hom.: 1 Cov.: 27 AF XY: 0.00149 AC XY: 110 AN XY: 73720

African (AFR) AF: 0.00557 AC: 229 AN: 41142

American (AMR) AF: 0.000592 AC: 9 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67656

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000141 Hom.: 95

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.041
Mutation Taster		=181/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3832728; hg19: chr11-47380276;