Genetic Variant SPI1:p.Leu232AlafsTer55 (chr11-47355345-AGC-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_003120.3(SPI1):c.693_694delGC(p.Leu232AlafsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPI1
NM_003120.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 3.49

Publications

2 publications found

Variant links:

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: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

SPI1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47355345-AGC-A is Pathogenic according to our data. Variant chr11-47355345-AGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 989449.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3 link	c.693_694delGC	p.Leu232AlafsTer55	frameshift_variant	Exon 5 of 5	ENST00000378538.8	NP_003111.2	P17947-1
SPI1	NM_001080547.2 link	c.696_697delGC	p.Leu233AlafsTer55	frameshift_variant	Exon 5 of 5		NP_001074016.1	P17947-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPI1	ENST00000378538.8 link	c.693_694delGC	p.Leu232AlafsTer55	frameshift_variant	Exon 5 of 5	1	NM_003120.3	ENSP00000367799.4		P17947-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249754

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461032

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726822

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111586

Other (OTH)

AF:

0.00

AC:

AN:

60330

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Agammaglobulinemia

Pathogenic:1

Aug 28, 2024

Neil Romberg Laboratory, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

PU.1-mutated agammaglobulinemia

Pathogenic:1

Dec 18, 2020

Neil Romberg Laboratory, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Agammaglobulinemia 10, autosomal dominant

Pathogenic:1

Jan 25, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over