1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAGAGAGAG
• rs35896485
• NM_005263.5:c.925-14_925-5dupCTCTCTCTCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-14_925-5dupCTCTCTCTCT variant causes a splice region, 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 0.066 (405 hom., cov: 0)
  • Exomes 𝑓: 0.038 (137 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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-C-CAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298183.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-14_925-5dupCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.925-5_925-4insCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-5_925-4insCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCTCTCTCT		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 9102 AN: 137926 Hom.: 402 Cov.: 0

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0582

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.0608

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0383 AC: 52045 AN: 1357718 Hom.: 137 Cov.: 0 AF XY: 0.0382 AC XY: 25735 AN XY: 674012

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0545

Gnomad4 EAS exome AF: 0.0236

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0686

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0375

GnomAD4 genome AF: 0.0660 AC: 9108 AN: 138036 Hom.: 405 Cov.: 0 AF XY: 0.0681 AC XY: 4517 AN XY: 66300

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0581

Gnomad4 SAS AF: 0.0555

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0743

Gnomad4 OTH AF: 0.0632

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe congenital neutropenia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GFI1-related disorder Benign:1

Mar 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;