11-47358725-GCACA-GCACACACACACACACTGGCAAACATTCACA

Variant names:

• chr11-47358725-G-GCACACACACACACACTGGCAAACATT
• rs3832728
• ENST00000533968.1:c.611_612insAATGTTTGCCAGTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000533968.1(SPI1):​c.611_612insAATGTTTGCCAGTGTGTGTGTGTGTG​(p.Cys204fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 150,902 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
• Consequence: SPI1 ENST00000533968.1 frameshift, stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410

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_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.172 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPI1	NM_003120.3	c.493+118_493+119insAATGTTTGCCAGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 4	ENST00000378538.8	NP_003111.2
SPI1	NM_001080547.2	c.496+118_496+119insAATGTTTGCCAGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 4		NP_001074016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPI1	ENST00000533968.1	c.611_612insAATGTTTGCCAGTGTGTGTGTGTGTG	p.Cys204fs	frameshift_variant, stop_gained	Exon 4 of 4	1		ENSP00000438846.1
SPI1	ENST00000378538.8	c.493+118_493+119insAATGTTTGCCAGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 4	1	NM_003120.3	ENSP00000367799.4
SPI1	ENST00000227163.8	c.496+118_496+119insAATGTTTGCCAGTGTGTGTGTGTGTG		intron_variant	Intron 4 of 4	2		ENSP00000227163.4
SPI1	ENST00000533030.1	c.46-3180_46-3179insAATGTTTGCCAGTGTGTGTGTGTGTG		intron_variant	Intron 1 of 1	2		ENSP00000443865.1

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150902 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 11

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150902 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 73598

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3832728; hg19: chr11-47380276;