1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAG

Position:

• chr1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_005263.5(GFI1):​c.925-16_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 0.000639 in 1,520,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B: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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-92478757-CAGAGAGAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAGAGAGAG-C is described in ClinVar as [Benign]. Clinvar id is 722828.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.925-16_925-5del		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.925-16_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_005263.5	ENSP00000294702	P1
GFI1	ENST00000370332.5	c.925-16_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000359357	P1
GFI1	ENST00000427103.6	c.925-16_925-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000399719	P1
GFI1	ENST00000696667.1	c.138+1579_138+1590del		intron_variant				ENSP00000512792

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 32 AN: 138178 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000709

Gnomad ASJ AF: 0.00238

Gnomad EAS AF: 0.000660

Gnomad SAS AF: 0.000514

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000680 AC: 940 AN: 1382278 Hom.: 0 AF XY: 0.000681 AC XY: 468 AN XY: 686834

Gnomad4 AFR exome AF: 0.000382

Gnomad4 AMR exome AF: 0.000818

Gnomad4 ASJ exome AF: 0.00196

Gnomad4 EAS exome AF: 0.000192

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.000502

Gnomad4 NFE exome AF: 0.000693

Gnomad4 OTH exome AF: 0.000785

GnomAD4 genome AF: 0.000231 AC: 32 AN: 138288 Hom.: 0 Cov.: 0 AF XY: 0.000256 AC XY: 17 AN XY: 66446

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.0000708

Gnomad4 ASJ AF: 0.00238

Gnomad4 EAS AF: 0.000661

Gnomad4 SAS AF: 0.000516

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000154

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

- -

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;