1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAGAGAGAGAGAG
• rs35896485
• NM_005263.5:c.925-18_925-5dupCTCTCTCTCTCTCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-18_925-5dupCTCTCTCTCTCTCT 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 0.011 (16 hom., cov: 0)
  • Exomes 𝑓: 0.0045 (26 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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-C-CAGAGAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAGAGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298181.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1584/138232) while in subpopulation AFR AF= 0.0223 (802/35928). AF 95% confidence interval is 0.021. There are 16 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-18_925-5dupCTCTCTCTCTCTCT		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_925-4insCTCTCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-5_925-4insCTCTCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCTCTCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCTCTCTCTCTCT		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1582 AN: 138122 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00118

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.00617

Gnomad FIN AF: 0.00559

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.00858

Gnomad OTH AF: 0.00786

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00448 AC: 6180 AN: 1379238 Hom.: 26 Cov.: 0 AF XY: 0.00446 AC XY: 3056 AN XY: 685272

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00361

Gnomad4 EAS exome AF: 0.00250

Gnomad4 SAS exome AF: 0.00542

Gnomad4 FIN exome AF: 0.00255

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.0115 AC: 1584 AN: 138232 Hom.: 16 Cov.: 0 AF XY: 0.0113 AC XY: 748 AN XY: 66406

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00638

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00353

Gnomad4 SAS AF: 0.00619

Gnomad4 FIN AF: 0.00559

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00777

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;