chr9-132990934-A-AC

Variant names:

• chr9-132990934-A-AC
• rs397989794
• NM_001377304.1:c.880dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001377304.1(GFI1B):​c.880dupC​(p.His294ProfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: GFI1B NM_001377304.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91
• Publications: 8 publications found

Genes affected

GFI1B (HGNC:4238): (growth factor independent 1B transcriptional repressor) This gene encodes a zinc-finger containing transcriptional regulator that is primarily expressed in cells of hematopoietic lineage. The encoded protein complexes with numerous other transcriptional regulatory proteins including GATA-1, runt-related transcription factor 1 and histone deacetylases to control expression of genes involved in the development and maturation of erythrocytes and megakaryocytes. Mutations in this gene are the cause of the autosomal dominant platelet disorder, platelet-type bleeding disorder-17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

GFI1B Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• platelet storage pool deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 0.113 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-132990934-A-AC is Pathogenic according to our data. Variant chr9-132990934-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 88891.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377304.1. 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
	GFI1B	NM_001377304.1	MANE Select	c.880dupC	p.His294ProfsTer14	frameshift	Exon 7 of 7	NP_001364233.1	Q5VTD9-1
	GFI1B	NM_001371908.1		c.946dupC	p.His316ProfsTer14	frameshift	Exon 7 of 7	NP_001358837.1	A0A024R8F3
	GFI1B	NM_004188.8		c.880dupC	p.His294ProfsTer14	frameshift	Exon 11 of 11	NP_004179.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1B	ENST00000372122.4	TSL:1 MANE Select	c.880dupC	p.His294ProfsTer14	frameshift	Exon 7 of 7	ENSP00000361195.1	Q5VTD9-1
	GFI1B	ENST00000339463.7	TSL:1	c.880dupC	p.His294ProfsTer14	frameshift	Exon 11 of 11	ENSP00000344782.3	Q5VTD9-1
	GFI1B	ENST00000636263.1	TSL:5	c.976dupC	p.His326ProfsTer14	frameshift	Exon 6 of 6	ENSP00000489646.1	A0A1B0GTD0

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Platelet-type bleeding disorder 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 8

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

Other links and lift over

dbSNP: rs397989794; hg19: chr9-135866321;