1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAGAGAG
• rs35896485
• NM_005263.5:c.925-12_925-5dupCTCTCTCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-12_925-5dupCTCTCTCT 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 0.064 (392 hom., cov: 0)
  • Exomes 𝑓: 0.053 (200 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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-CAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298180.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-12_925-5dupCTCTCTCT		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_925-4insCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.925-5_925-4insCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.925-5_925-4insCTCTCTCT		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1590_138+1591insCTCTCTCT		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 8882 AN: 138040 Hom.: 393 Cov.: 0

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.0320

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0685

Gnomad NFE AF: 0.0515

Gnomad OTH AF: 0.0514

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0531 AC: 72175 AN: 1358346 Hom.: 200 Cov.: 0 AF XY: 0.0531 AC XY: 35848 AN XY: 674840

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.0529

Gnomad4 ASJ exome AF: 0.0729

Gnomad4 EAS exome AF: 0.0744

Gnomad4 SAS exome AF: 0.0621

Gnomad4 FIN exome AF: 0.0562

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0558

GnomAD4 genome AF: 0.0643 AC: 8885 AN: 138150 Hom.: 392 Cov.: 0 AF XY: 0.0642 AC XY: 4265 AN XY: 66386

Gnomad4 AFR AF: 0.0807

Gnomad4 AMR AF: 0.0678

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.0704

Gnomad4 FIN AF: 0.0495

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0513

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

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

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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;