1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005263.5(GFI1):c.925-5_925-4insCTCTCTCTCTCTCTCT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.17

Genes affected

GFI1 (HGNC:4237): (growth factor independent 1 transcriptional repressor) This gene encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including hematopoiesis and oncogenesis. It functions as part of a complex along with other cofactors to control histone modifications that lead to silencing of the target gene promoters. Mutations in this gene cause autosomal dominant severe congenital neutropenia, and also dominant nonimmune chronic idiopathic neutropenia of adults, which are heterogeneous hematopoietic disorders that cause predispositions to leukemias and infections. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 1-92478757-C-CAGAGAGAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAGAGAGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 488 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCTCTCTCTCTCTCT		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 488 AN: 138140 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00156

Gnomad ASJ AF: 0.00268

Gnomad EAS AF: 0.000880

Gnomad SAS AF: 0.00257

Gnomad FIN AF: 0.00128

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00164 AC: 2264 AN: 1381224 Hom.: 7 Cov.: 0 AF XY: 0.00161 AC XY: 1103 AN XY: 686270

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.000815

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00354 AC: 489 AN: 138250 Hom.: 4 Cov.: 0 AF XY: 0.00322 AC XY: 214 AN XY: 66424

Gnomad4 AFR AF: 0.00540

Gnomad4 AMR AF: 0.00156

Gnomad4 ASJ AF: 0.00268

Gnomad4 EAS AF: 0.000882

Gnomad4 SAS AF: 0.00258

Gnomad4 FIN AF: 0.00128

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2021

- -

GFI1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

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: rs35896485; hg19: chr1-92944314;