1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAG

Variant summary

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

The NM_005263.5(GFI1):​c.925-5_925-4insCT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (949 hom., cov: 0)
  • Exomes 𝑓: 0.066 (53 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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-C-CAG is Benign according to our data. Variant chr1-92478757-C-CAG is described in ClinVar as [Likely_benign]. Clinvar id is 402897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-5_925-4insCT		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.925-5_925-4insCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-5_925-4insCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-5_925-4insCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCT		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 13491 AN: 137960 Hom.: 948 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0142

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.0640

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0539

Gnomad OTH AF: 0.0912

GnomAD4 exome AF: 0.0659 AC: 88579 AN: 1344604 Hom.: 53 Cov.: 0 AF XY: 0.0661 AC XY: 44126 AN XY: 667500

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0821

Gnomad4 ASJ exome AF: 0.0599

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0792

Gnomad4 FIN exome AF: 0.0584

Gnomad4 NFE exome AF: 0.0594

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.0978 AC: 13498 AN: 138066 Hom.: 949 Cov.: 0 AF XY: 0.0973 AC XY: 6451 AN XY: 66332

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.0943

Gnomad4 ASJ AF: 0.0625

Gnomad4 EAS AF: 0.0919

Gnomad4 SAS AF: 0.0573

Gnomad4 FIN AF: 0.0640

Gnomad4 NFE AF: 0.0539

Gnomad4 OTH AF: 0.0917

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

GFI1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

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). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

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;