Genetic Variant SPI1:p.Pro268Gln (chr11-47355237-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003120.3(SPI1):c.803C>A(p.Pro268Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000787 in 1,271,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

SPI1
NM_003120.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088633716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3 link	c.803C>A	p.Pro268Gln	missense_variant	Exon 5 of 5	ENST00000378538.8	NP_003111.2	P17947-1
SPI1	NM_001080547.2 link	c.806C>A	p.Pro269Gln	missense_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.803C>A	p.Pro268Gln	missense_variant	Exon 5 of 5	1	NM_003120.3	ENSP00000367799.4		P17947-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

55356

AF XY:

0.00

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:

0.00

GnomAD4 exome

AF:

7.87e-7

AC:

AN:

1271080

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

619652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25786

American (AMR)

AF:

0.00

AC:

AN:

21078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19272

East Asian (EAS)

AF:

0.00

AC:

AN:

29914

South Asian (SAS)

AF:

0.00

AC:

AN:

61190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5204

European-Non Finnish (NFE)

AF:

9.77e-7

AC:

AN:

1023542

Other (OTH)

AF:

0.00

AC:

AN:

52480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.806C>A (p.P269Q) alteration is located in exon 5 (coding exon 5) of the SPI1 gene. This alteration results from a C to A substitution at nucleotide position 806, causing the proline (P) at amino acid position 269 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.

PhyloP100

1.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.039

Sift

Benign

0.36

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0

B;B

Vest4

0.096

MutPred

0.35

Loss of glycosylation at P268 (P = 0.0057);.;

MVP

0.42

MPC

1.6

ClinPred

0.19

GERP RS

3.1

Varity_R

0.061

gMVP

0.58

Mutation Taster

=94/6

polymorphism

(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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11-47355237-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over