Genetic Variant SPI1:p.Pro268Ser (chr11-47355238-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_003120.3(SPI1):c.802C>T(p.Pro268Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000784 in 1,275,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

SPI1
NM_003120.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.77

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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087263554).

BP6

Variant 11-47355238-G-A is Benign according to our data. Variant chr11-47355238-G-A is described in ClinVar as [Benign]. Clinvar id is 3341199.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3 link	c.802C>T	p.Pro268Ser	missense_variant	Exon 5 of 5	ENST00000378538.8	NP_003111.2	P17947-1
SPI1	NM_001080547.2 link	c.805C>T	p.Pro269Ser	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.802C>T	p.Pro268Ser	missense_variant	Exon 5 of 5	1	NM_003120.3	ENSP00000367799.4		P17947-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000173

AC:

AN:

57968

AF XY:

0.0000335

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000883

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:

7.84e-7

AC:

AN:

1275374

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

621944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25952

American (AMR)

AF:

0.0000458

AC:

AN:

21846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19412

East Asian (EAS)

AF:

0.00

AC:

AN:

30094

South Asian (SAS)

AF:

0.00

AC:

AN:

61778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1025598

Other (OTH)

AF:

0.00

AC:

AN:

52690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Agammaglobulinemia

Benign:1

Aug 28, 2024

Neil Romberg Laboratory, Children's Hospital of Philadelphia

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.087

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.

PhyloP100

3.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.020

Sift

Benign

0.48

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.019

B;B

Vest4

0.098

MutPred

0.38

Gain of phosphorylation at P268 (P = 0.0031);.;

MVP

0.49

MPC

2.0

ClinPred

0.084

GERP RS

2.2

Varity_R

0.049

gMVP

0.60

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over