1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-CAGAGAG-C
• rs35896485
• NM_005263.5:c.925-10_925-5delCTCTCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005263.5(GFI1):​c.925-10_925-5delCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,516,400 control chromosomes in the GnomAD database, including 1,297 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (941 hom., cov: 0)
  • Exomes 𝑓: 0.11 (356 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• 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 -16 ACMG points.

• BP6: Variant 1-92478757-CAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 298185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92478757-CAGAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAGAG-C is described in Lovd as [Benign]. Variant chr1-92478757-CAGAGAG-C is described in Lovd as [Likely_benign]. Variant chr1-92478757-CAGAGAG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-10_925-5delCTCTCT		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.925-10_925-5delCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-10_925-5delCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-10_925-5delCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1585_138+1590delCTCTCT		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 15361 AN: 138130 Hom.: 941 Cov.: 0

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0616

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.147

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.111 AC: 153606 AN: 1378160 Hom.: 356 AF XY: 0.111 AC XY: 76269 AN XY: 684712

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.0883

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.111 AC: 15376 AN: 138240 Hom.: 941 Cov.: 0 AF XY: 0.113 AC XY: 7507 AN XY: 66424

Gnomad4 AFR AF: 0.0620

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.0254

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe congenital neutropenia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Mar 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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;