11-47358725-GCACA-GCACACACA

Variant names:

• chr11-47358725-G-GCACA
• rs3832728
• ENST00000533968.1:c.608_611dupTGTG

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_611dupTGTG​(p.Met205ValfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 943,134 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 0.00023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00018 (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 0.172 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 = 0.000225 (34/151008) while in subpopulation AFR AF = 0.000583 (24/41142). AF 95% confidence interval is 0.000402. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 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+118dupTGTG		intron	N/A	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.496+115_496+118dupTGTG		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_611dupTGTG	p.Met205ValfsTer52	frameshift	Exon 4 of 4	ENSP00000438846.1	F5H3K6
	SPI1	ENST00000378538.8	TSL:1 MANE Select	c.493+115_493+118dupTGTG		intron	N/A	ENSP00000367799.4	P17947-1
	SPI1	ENST00000227163.8	TSL:2	c.496+115_496+118dupTGTG		intron	N/A	ENSP00000227163.4	P17947-2

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 34 AN: 150896 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000123 AC: 15 AN: 121646 AF XY: 0.000137

Gnomad AFR exome AF: 0.000504

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.000539

GnomAD4 exome AF: 0.000175 AC: 139 AN: 792126 Hom.: 0 Cov.: 11 AF XY: 0.000151 AC XY: 62 AN XY: 411552

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

African (AFR) AF: 0.000762 AC: 15 AN: 19690

American (AMR) AF: 0.000176 AC: 6 AN: 34130

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

East Asian (EAS) AF: 0.000187 AC: 6 AN: 32052

South Asian (SAS) AF: 0.0000904 AC: 6 AN: 66362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34928

Middle Eastern (MID) AF: 0.000220 AC: 1 AN: 4542

European-Non Finnish (NFE) AF: 0.000161 AC: 87 AN: 541340

Other (OTH) AF: 0.000473 AC: 18 AN: 38034

⚠️ 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: 0.000225 AC: 34 AN: 151008 Hom.: 0 Cov.: 27 AF XY: 0.000163 AC XY: 12 AN XY: 73718

African (AFR) AF: 0.000583 AC: 24 AN: 41142

American (AMR) AF: 0.000263 AC: 4 AN: 15196

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

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5104

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

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

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67654

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000188 Hom.: 95

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.041
Mutation Taster		=152/48	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3832728; hg19: chr11-47380276;