11-47355238-G-T

Position:

• chr11-47355238-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003120.3(SPI1):​c.802C>A​(p.Pro268Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPI1 NM_003120.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.77

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.09676713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPI1	NM_003120.3	c.802C>A	p.Pro268Thr	missense_variant	5/5	ENST00000378538.8
SPI1	NM_001080547.2	c.805C>A	p.Pro269Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPI1	ENST00000378538.8	c.802C>A	p.Pro268Thr	missense_variant	5/5	1	NM_003120.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SPI1-related condition Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The SPI1 c.805C>A variant is predicted to result in the amino acid substitution p.Pro269Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.023
Sift	Benign	0.45	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.037	B;B
Vest4		0.082
MutPred		0.38		Gain of phosphorylation at P268 (P = 0.0065);.;
MVP		0.53
MPC		2.3
ClinPred		0.26	T
GERP RS		2.2
Varity_R		0.074
gMVP		0.58

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: chr11-47376789;