11-47359855-G-A

Position:

• chr11-47359855-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_003120.3(SPI1):​c.328C>T​(p.Gln110Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPI1 NM_003120.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.73

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-47359855-G-A is Pathogenic according to our data. Variant chr11-47359855-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 989450.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPI1	NM_003120.3	c.328C>T	p.Gln110Ter	stop_gained, splice_region_variant	3/5	ENST00000378538.8
SPI1	NM_001080547.2	c.331C>T	p.Gln111Ter	stop_gained, splice_region_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPI1	ENST00000378538.8	c.328C>T	p.Gln110Ter	stop_gained, splice_region_variant	3/5	1	NM_003120.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 10, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 22, 2022	This variant is interpreted as pathogenic for Agammaglobulinemia 10, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Assumed de novo, but without confirmation of paternity and maternity (PM6); Predicted nullvariant in a gene where LOF is a known mechanism of disease (PVS1 downgraded to strong); Well-established functional studies show a deleterious effect (PS3). -

PU.1-mutated agammaglobulinemia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Neil Romberg Laboratory, Children's Hospital of Philadelphia

Dec 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	52
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;D;D
Vest4		0.97
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47381406;