1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAG

Variant summary

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

The NM_005263.5(GFI1):​c.925-14_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 0.0172 in 1,519,596 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (13 hom., cov: 0)
  • Exomes 𝑓: 0.017 (16 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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-CAGAGAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAGAGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298186.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr1-92478757-CAGAGAGAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAGAGAGAG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2098/138278) while in subpopulation NFE AF= 0.0194 (1255/64796). AF 95% confidence interval is 0.0185. There are 13 homozygotes in gnomad4. There are 996 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2098 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-14_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.925-14_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-14_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-14_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1581_138+1590del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2098 AN: 138170 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00926

Gnomad AMI AF: 0.0142

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.00418

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0178

GnomAD4 exome AF: 0.0174 AC: 24029 AN: 1381318 Hom.: 16 AF XY: 0.0168 AC XY: 11510 AN XY: 686374

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.00275

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0152 AC: 2098 AN: 138278 Hom.: 13 Cov.: 0 AF XY: 0.0150 AC XY: 996 AN XY: 66442

Gnomad4 AFR AF: 0.00920

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.0238

Gnomad4 EAS AF: 0.00419

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.0176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2021	Variant summary: GFI1 c.925-14_925-5del10 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.015 in 137034 control chromosomes in the gnomAD database v3.1 genomes dataset, including 14 homozygotes, strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.925-14_925-5del10 in individuals affected with Severe Congenital Neutropenia 2, Autosomal Dominant and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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 29, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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- -

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;