11-47355240-T-G

Variant names:

• chr11-47355240-T-G
• rs976789974
• NM_003120.3:c.800A>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_003120.3(SPI1):​c.800A>C​(p.His267Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPI1 NM_003120.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.02

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12776956).
• BP6: Variant 11-47355240-T-G is Benign according to our data. Variant chr11-47355240-T-G is described in ClinVar as [Benign]. Clinvar id is 3341198.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	c.800A>C	p.His267Pro	missense_variant	Exon 5 of 5	ENST00000378538.8	NP_003111.2
SPI1	NM_001080547.2	c.803A>C	p.His268Pro	missense_variant	Exon 5 of 5		NP_001074016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPI1	ENST00000378538.8	c.800A>C	p.His267Pro	missense_variant	Exon 5 of 5	1	NM_003120.3	ENSP00000367799.4
SPI1	ENST00000227163.8	c.803A>C	p.His268Pro	missense_variant	Exon 5 of 5	2		ENSP00000227163.4
SPI1	ENST00000533030.1	c.*244A>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000443865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.87e-7 AC: 1 AN: 1269996 Hom.: 0 Cov.: 31 AF XY: 0.00000162 AC XY: 1 AN XY: 618928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.033
Sift	Benign	0.032	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.35		Gain of glycosylation at H267 (P = 0.0042);.;
MVP		0.34
MPC		2.8
ClinPred		0.058	T
GERP RS		0.069
Varity_R		0.21
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs976789974; hg19: chr11-47376791; COSMIC: COSV57031845; COSMIC: COSV57031845;