1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005263.5(GFI1):​c.925-8_925-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,373,978 control chromosomes in the GnomAD database, including 16 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (21 hom., cov: 0)
  • Exomes 𝑓: 0.032 (16 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 Benign. Variant got -9 ACMG points.

• BP6: Variant 1-92478757-CAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298184.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chr1-92478757-CAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAG-C is described in Lovd as [Benign]. Variant chr1-92478757-CAGAG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.032 (43945/1373978) while in subpopulation AFR AF= 0.0383 (1197/31240). AF 95% confidence interval is 0.0365. There are 16 homozygotes in gnomad4_exome. There are 21584 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 43945 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-8_925-5del		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.925-8_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-8_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-8_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1587_138+1590del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2493 AN: 138140 Hom.: 21 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00572

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0171

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0194

GnomAD4 exome AF: 0.0320 AC: 43945 AN: 1373978 Hom.: 16 AF XY: 0.0316 AC XY: 21584 AN XY: 682668

Gnomad4 AFR exome AF: 0.0383

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0356

Gnomad4 EAS exome AF: 0.00636

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.0355

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0181 AC: 2497 AN: 138248 Hom.: 21 Cov.: 0 AF XY: 0.0185 AC XY: 1228 AN XY: 66428

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00573

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0192

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe congenital neutropenia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 09, 2022

This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID: 298184). Evolutionary conservation and computational prediction tools for this variant are limited or unavailable. This variant is a deletion of 4 nucleotides in a repetitive region within the intron. Splice prediction tools do not suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

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: rs35896485; hg19: chr1-92944314;