1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAG
• rs35896485
• NM_005263.5:c.925-8_925-5dupCTCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-8_925-5dupCTCT 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 0.054 (334 hom., cov: 0)
  • Exomes 𝑓: 0.11 (120 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, 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-C-CAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-8_925-5dupCTCT		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_925-4insCTCT		splice_region_variant, intron_variant	Intron 5 of 6	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-5_925-4insCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCT		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 7431 AN: 137984 Hom.: 333 Cov.: 0

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00711

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0143

Gnomad EAS AF: 0.0750

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.0342

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.111 AC: 147313 AN: 1327218 Hom.: 120 Cov.: 0 AF XY: 0.113 AC XY: 74432 AN XY: 659168

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0871

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0539 AC: 7447 AN: 138092 Hom.: 334 Cov.: 0 AF XY: 0.0536 AC XY: 3555 AN XY: 66346

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0369

Gnomad4 ASJ AF: 0.0143

Gnomad4 EAS AF: 0.0747

Gnomad4 SAS AF: 0.0444

Gnomad4 FIN AF: 0.0196

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

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

Significance: Benign

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

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

May 05, 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;