chr11-47358725-G-GCA

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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3	c.493+117_493+118dupTG		intron_variant	Intron 4 of 4	ENST00000378538.8	NP_003111.2
SPI1	NM_001080547.2	c.496+117_496+118dupTG		intron_variant	Intron 4 of 4		NP_001074016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPI1	ENST00000533968.1	c.610_611dupTG	p.Met205AlafsTer24	frameshift_variant	Exon 4 of 4	1		ENSP00000438846.1
SPI1	ENST00000378538.8	c.493+117_493+118dupTG		intron_variant	Intron 4 of 4	1	NM_003120.3	ENSP00000367799.4
SPI1	ENST00000227163.8	c.496+117_496+118dupTG		intron_variant	Intron 4 of 4	2		ENSP00000227163.4
SPI1	ENST00000533030.1	c.46-3181_46-3180dupTG		intron_variant	Intron 1 of 1	2		ENSP00000443865.1

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

Gnomad4 AFR exome AF: 0.282 AC: 5559 AN: 19690

Gnomad4 AMR exome AF: 0.273 AC: 9327 AN: 34134

Gnomad4 ASJ exome AF: 0.127 AC: 2672 AN: 21006

Gnomad4 EAS exome AF: 0.345 AC: 11055 AN: 32056

Gnomad4 SAS exome AF: 0.170 AC: 11240 AN: 66290

Gnomad4 FIN exome AF: 0.216 AC: 7537 AN: 34890

Gnomad4 NFE exome AF: 0.120 AC: 64665 AN: 539062

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.335 AC: 0.334509 AN: 0.334509

Gnomad4 AMR AF: 0.228 AC: 0.22774 AN: 0.22774

Gnomad4 ASJ AF: 0.135 AC: 0.135127 AN: 0.135127

Gnomad4 EAS AF: 0.330 AC: 0.329871 AN: 0.329871

Gnomad4 SAS AF: 0.174 AC: 0.174428 AN: 0.174428

Gnomad4 FIN AF: 0.264 AC: 0.264412 AN: 0.264412

Gnomad4 NFE AF: 0.142 AC: 0.141752 AN: 0.141752

Gnomad4 OTH AF: 0.172 AC: 0.172053 AN: 0.172053

Alfa AF: 0.0892 Hom.: 95

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3832728; hg19: chr11-47380276; COSMIC: COSV57045877;