1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005263.5(GFI1):c.925-6_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 0.118 in 1,507,098 control chromosomes in the GnomAD database, including 1,344 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 0.12 (1084 hom., cov: 0)
  • Exomes 𝑓: 0.12 (260 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• 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-CAG-C is Benign according to our data. Variant chr1-92478757-CAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298182.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2}. Variant chr1-92478757-CAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAG-C is described in Lovd as [Benign]. Variant chr1-92478757-CAG-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-6_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.925-6_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-6_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-6_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1589_138+1590del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.123 AC: 17031 AN: 138020 Hom.: 1087 Cov.: 0

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0301

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.117 AC: 160236 AN: 1368968 Hom.: 260 AF XY: 0.115 AC XY: 78131 AN XY: 680242

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0644

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0255

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.123 AC: 17049 AN: 138130 Hom.: 1084 Cov.: 0 AF XY: 0.122 AC XY: 8126 AN XY: 66374

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.0302

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.133

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe congenital neutropenia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, 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 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

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;