11-47355318-A-C

Variant names:

• chr11-47355318-A-C
• rs2095906404
• NM_003120.3:c.722T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003120.3(SPI1):​c.722T>G​(p.Val241Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPI1 NM_003120.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.10

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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• PP5: Variant 11-47355318-A-C is Pathogenic according to our data. Variant chr11-47355318-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 801321.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3	c.722T>G	p.Val241Gly	missense_variant	Exon 5 of 5	ENST00000378538.8	NP_003111.2
SPI1	NM_001080547.2	c.725T>G	p.Val242Gly	missense_variant	Exon 5 of 5		NP_001074016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPI1	ENST00000378538.8	c.722T>G	p.Val241Gly	missense_variant	Exon 5 of 5	1	NM_003120.3	ENSP00000367799.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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 10, 2019

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

Jun 22, 2022

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Well-established functional studies show a deleterious effect (PS3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		9.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.57		Loss of stability (P = 0.0069);.;
MVP		0.84
MPC		3.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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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Other links and lift over

dbSNP: rs2095906404; hg19: chr11-47376869;