1-92478757-CAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant summary

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

The NM_005263.5(GFI1):c.925-5_925-4insCTCTCTCTCTCTCTCTCT 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 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00024 (1 hom.)
  • Failed GnomAD Quality Control
• 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-C-CAGAGAGAGAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAGAGAGAGAG is described in ClinVar as [Benign]. Clinvar id is 788327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 213 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 213 AN: 138164 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00118

Gnomad AMR AF: 0.000709

Gnomad ASJ AF: 0.000596

Gnomad EAS AF: 0.000660

Gnomad SAS AF: 0.000257

Gnomad FIN AF: 0.000233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000494

Gnomad OTH AF: 0.00209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000245 AC: 338 AN: 1382350 Hom.: 1 Cov.: 0 AF XY: 0.000247 AC XY: 170 AN XY: 686876

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.000383

Gnomad4 ASJ exome AF: 0.000160

Gnomad4 EAS exome AF: 0.000357

Gnomad4 SAS exome AF: 0.000277

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000296

GnomAD4 genome AF: 0.00155 AC: 214 AN: 138272 Hom.: 0 Cov.: 0 AF XY: 0.00146 AC XY: 97 AN XY: 66442

Gnomad4 AFR AF: 0.00442

Gnomad4 AMR AF: 0.000708

Gnomad4 ASJ AF: 0.000596

Gnomad4 EAS AF: 0.000661

Gnomad4 SAS AF: 0.000258

Gnomad4 FIN AF: 0.000233

Gnomad4 NFE AF: 0.000494

Gnomad4 OTH AF: 0.00207

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

Invitae

Dec 06, 2022

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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;