1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005263.5(GFI1):​c.925-12_925-5delCTCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,515,336 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (4 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter 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 -10 ACMG points.

• BP6: Variant 1-92478757-CAGAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAGAG-C is described in ClinVar as [Benign]. Clinvar id is 470696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-92478757-CAGAGAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAGAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAGAGAG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0115 (15786/1377086) while in subpopulation MID AF= 0.018 (75/4162). AF 95% confidence interval is 0.0166. There are 4 homozygotes in gnomad4_exome. There are 8132 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-12_925-5delCTCTCTCT		splice_region_variant, intron_variant		ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.925-12_925-5delCTCTCTCT		splice_region_variant, intron_variant		2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-12_925-5delCTCTCTCT		splice_region_variant, intron_variant		1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-12_925-5delCTCTCTCT		splice_region_variant, intron_variant		1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1583_138+1590delCTCTCTCT		intron_variant				ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 174 AN: 138140 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000893

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00154

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000818

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0115 AC: 15786 AN: 1377086 Hom.: 4 AF XY: 0.0119 AC XY: 8132 AN XY: 684258

Gnomad4 AFR exome AF: 0.00593

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.00125 AC: 173 AN: 138250 Hom.: 0 Cov.: 0 AF XY: 0.00120 AC XY: 80 AN XY: 66426

Gnomad4 AFR AF: 0.00247

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000893

Gnomad4 EAS AF: 0.000220

Gnomad4 SAS AF: 0.00129

Gnomad4 FIN AF: 0.00117

Gnomad4 NFE AF: 0.000818

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 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;