1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAG

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_925-4insCTCTCT 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7892 hom., cov: 0)
  • Exomes 𝑓: 0.25 (1014 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: 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-C-CAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAG is described in ClinVar as [Benign]. Clinvar id is 1170883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-5_925-4insCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.925-5_925-4insCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	ENSP00000294702	P1
GFI1	ENST00000370332.5	c.925-5_925-4insCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000359357	P1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCTCT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000399719	P1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCTCT		intron_variant				ENSP00000512792

Frequencies

GnomAD3 genomes AF: 0.323 AC: 44487 AN: 137834 Hom.: 7898 Cov.: 0

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.305

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.321

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.248 AC: 329767 AN: 1329534 Hom.: 1014 Cov.: 0 AF XY: 0.249 AC XY: 164605 AN XY: 660456

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.323 AC: 44496 AN: 137940 Hom.: 7892 Cov.: 0 AF XY: 0.321 AC XY: 21288 AN XY: 66258

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.518

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.319

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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	- -
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. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

GFI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 11, 2020

This variant is classified as 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 18, 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;