Genetic Variant ENST00000533968.1:c.606_611dupTGTGTG (chr11-47358725-G-GCACACA) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The ENST00000533968.1(SPI1):c.606_611dupTGTGTG(p.Cys204_Met205insValCys) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 943,314 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)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

SPI1
ENST00000533968.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0410

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

agammaglobulinemia 10, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

SPI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000533968.1.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000533968.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPI1	NM_003120.3	MANE Select	c.493+113_493+118dupTGTGTG		intron	N/A	NP_003111.2	P17947-1
	SPI1	NM_001080547.2		c.496+113_496+118dupTGTGTG		intron	N/A	NP_001074016.1	P17947-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPI1	ENST00000533968.1	TSL:1	c.606_611dupTGTGTG	p.Cys204_Met205insValCys	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000438846.1	F5H3K6
SPI1	ENST00000378538.8	TSL:1 MANE Select	c.493+113_493+118dupTGTGTG		intron	N/A	ENSP00000367799.4	P17947-1
SPI1	ENST00000227163.8	TSL:2	c.496+113_496+118dupTGTGTG		intron	N/A	ENSP00000227163.4	P17947-2

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000822

AC:

AN:

121646

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000379

AC:

AN:

792412

Hom.:

Cov.:

AF XY:

0.00000243

AC XY:

AN XY:

411692

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000507

AC:

AN:

19714

American (AMR)

AF:

0.00

AC:

AN:

34154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21050

East Asian (EAS)

AF:

0.0000312

AC:

AN:

32076

South Asian (SAS)

AF:

0.00

AC:

AN:

66388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4542

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

541508

Other (OTH)

AF:

0.00

AC:

AN:

38040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000965894), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73598

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41020

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67664

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.041

Mutation Taster

=86/14

polymorphism

(source)

Splicing

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

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over