1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAG

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_925-5del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, 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/exons	MANE	UniProt
GFI1	NM_005263.5	c.925-10_925-5del		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.925-10_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.925-10_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000427103.6	c.925-10_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
GFI1	ENST00000696667.1	c.138+1585_138+1590del		intron_variant

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

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Severe congenital neutropenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Mar 08, 2022

- -

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;