Genetic Variant SPI1:p.Arg230Pro (chr11-47355351-C-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

SPI1
NM_003120.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.68

Publications

0 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: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

SPI1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2672188.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPI1	NM_003120.3	MANE Select	c.689G>C	p.Arg230Pro	missense	Exon 5 of 5	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.692G>C	p.Arg231Pro	missense	Exon 5 of 5	NP_001074016.1	P17947-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPI1	ENST00000378538.8	TSL:1 MANE Select	c.689G>C	p.Arg230Pro	missense	Exon 5 of 5	ENSP00000367799.4	P17947-1
SPI1	ENST00000227163.8	TSL:2	c.692G>C	p.Arg231Pro	missense	Exon 5 of 5	ENSP00000227163.4	P17947-2
SPI1	ENST00000713543.1		c.428G>C	p.Arg143Pro	missense	Exon 7 of 7	ENSP00000518839.1	A0AAA9YHK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Agammaglobulinemia 10, autosomal dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.012

MutationAssessor

Pathogenic

3.3

PhyloP100

7.7

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.87

Gain of glycosylation at R230 (P = 0.0421)

MVP

0.93

MPC

3.7

ClinPred

1.0

GERP RS

4.1

Varity_R

0.95

gMVP

0.98

Mutation Taster

=3/97

disease causing

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over