11-47355351-C-G

Position:

• chr11-47355351-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003120.3(SPI1):​c.689G>C​(p.Arg230Pro) 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. 12/21 in silico tools predict a damaging 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:1
• Conservation: PhyloP100: 7.68

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 10 ACMG points.

• PM1: In a chain Transcription factor PU.1 (size 269) in uniprot entity SPI1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003120.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 11-47355351-C-G is Pathogenic according to our data. Variant chr11-47355351-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2672188.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.689G>C	p.Arg230Pro	missense_variant	5/5	ENST00000378538.8
SPI1	NM_001080547.2	c.692G>C	p.Arg231Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPI1	ENST00000378538.8	c.689G>C	p.Arg230Pro	missense_variant	5/5	1	NM_003120.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 10, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jul 26, 2023

The SPI1 c.689G>C (p.Arg230Pro) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The arginine at this codon occurs in the ETS domain, responsible for DNA binding, and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SPI1 function. In support of this prediction, functional studies show substitution of this arginine results in decreased immune system activation, indicating that this variant impacts protein function (Ha SD et al., PMID: 31586032). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.87		Gain of glycosylation at R230 (P = 0.0421);.;
MVP		0.93
MPC		3.7
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47376902; COSMIC: COSV57025945; COSMIC: COSV57025945;