11-47358725-GCACA-GCACACA

Variant names:

• chr11-47358725-G-GCA
• rs3832728
• ENST00000533968.1:c.610_611dupTG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BA1

The ENST00000533968.1(SPI1):​c.610_611dupTG​(p.Met205AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 940,472 control chromosomes in the GnomAD database, including 9,290 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4234 hom., cov: 27)
  • Exomes 𝑓: 0.15 (5056 hom.)
• Consequence: SPI1 ENST00000533968.1 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -6 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.
• BP6: Variant 11-47358725-G-GCA is Benign according to our data. Variant chr11-47358725-G-GCA is described in ClinVar as Benign. ClinVar VariationId is 2688186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

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+118dupTG		intron	N/A	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.496+117_496+118dupTG		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_611dupTG	p.Met205AlafsTer24	frameshift	Exon 4 of 4	ENSP00000438846.1	F5H3K6
	SPI1	ENST00000378538.8	TSL:1 MANE Select	c.493+117_493+118dupTG		intron	N/A	ENSP00000367799.4	P17947-1
	SPI1	ENST00000227163.8	TSL:2	c.496+117_496+118dupTG		intron	N/A	ENSP00000227163.4	P17947-2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 32995 AN: 150802 Hom.: 4235 Cov.: 27

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.208 AC: 25255 AN: 121646 AF XY: 0.199

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.150 AC: 118168 AN: 789558 Hom.: 5056 Cov.: 11 AF XY: 0.149 AC XY: 61260 AN XY: 410274

African (AFR) AF: 0.282 AC: 5559 AN: 19690

American (AMR) AF: 0.273 AC: 9327 AN: 34134

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 2672 AN: 21006

East Asian (EAS) AF: 0.345 AC: 11055 AN: 32056

South Asian (SAS) AF: 0.170 AC: 11240 AN: 66290

European-Finnish (FIN) AF: 0.216 AC: 7537 AN: 34890

Middle Eastern (MID) AF: 0.116 AC: 526 AN: 4522

European-Non Finnish (NFE) AF: 0.120 AC: 64665 AN: 539062

Other (OTH) AF: 0.147 AC: 5587 AN: 37908

GnomAD4 genome AF: 0.219 AC: 33004 AN: 150914 Hom.: 4234 Cov.: 27 AF XY: 0.225 AC XY: 16574 AN XY: 73666

African (AFR) AF: 0.335 AC: 13749 AN: 41102

American (AMR) AF: 0.228 AC: 3458 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 467 AN: 3456

East Asian (EAS) AF: 0.330 AC: 1683 AN: 5102

South Asian (SAS) AF: 0.174 AC: 824 AN: 4724

European-Finnish (FIN) AF: 0.264 AC: 2752 AN: 10408

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.142 AC: 9587 AN: 67632

Other (OTH) AF: 0.172 AC: 362 AN: 2104

Alfa AF: 0.0892 Hom.: 95

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.041
Mutation Taster		=191/9	polymorphism (auto)

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; COSMIC: COSV57045877;