11-47358725-GCACA-GCA

Variant names:

• chr11-47358725-GCA-G
• rs3832728
• ENST00000533968.1:c.610_611delTG

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.610_611delTG​(p.Cys204HisfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 918,092 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0030 (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 0.173 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000272 (41/150980) while in subpopulation AMR AF = 0.000724 (11/15196). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 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+117_493+118delTG		intron	N/A	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.496+117_496+118delTG		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.610_611delTG	p.Cys204HisfsTer51	frameshift	Exon 4 of 4	ENSP00000438846.1	F5H3K6
	SPI1	ENST00000378538.8	TSL:1 MANE Select	c.493+117_493+118delTG		intron	N/A	ENSP00000367799.4	P17947-1
	SPI1	ENST00000227163.8	TSL:2	c.496+117_496+118delTG		intron	N/A	ENSP00000227163.4	P17947-2

Frequencies

GnomAD3 genomes AF: 0.000272 AC: 41 AN: 150868 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000725

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 126 AN: 121646 AF XY: 0.00100

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.000539

GnomAD4 exome AF: 0.00302 AC: 2313 AN: 767112 Hom.: 0 AF XY: 0.00268 AC XY: 1067 AN XY: 398244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00176 AC: 34 AN: 19328

American (AMR) AF: 0.000298 AC: 10 AN: 33510

Ashkenazi Jewish (ASJ) AF: 0.000785 AC: 16 AN: 20372

East Asian (EAS) AF: 0.000127 AC: 4 AN: 31464

South Asian (SAS) AF: 0.000969 AC: 62 AN: 63952

European-Finnish (FIN) AF: 0.000471 AC: 16 AN: 33972

Middle Eastern (MID) AF: 0.000902 AC: 4 AN: 4436

European-Non Finnish (NFE) AF: 0.00396 AC: 2073 AN: 523308

Other (OTH) AF: 0.00256 AC: 94 AN: 36770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000272 AC: 41 AN: 150980 Hom.: 0 Cov.: 27 AF XY: 0.000258 AC XY: 19 AN XY: 73698

African (AFR) AF: 0.000316 AC: 13 AN: 41142

American (AMR) AF: 0.000724 AC: 11 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

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

South Asian (SAS) AF: 0.000423 AC: 2 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

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

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67636

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0116 Hom.: 95

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.041
Mutation Taster		=163/37	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: rs3832728; hg19: chr11-47380276; COSMIC: COSV57044305;