1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_005263.5(GFI1):​c.925-12_925-5delCTCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,515,336 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (4 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 3.17
• Publications: 2 publications found

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]

GFI1 Gene-Disease associations (from GenCC):

• neutropenia, severe congenital, 2, autosomal dominant

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• severe congenital neutropenia

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-92478757-CAGAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAGAG-C is described in ClinVar as Benign. ClinVar VariationId is 470696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 173 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005263.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	NM_005263.5	MANE Select	c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	NP_001120688.1	Q99684

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	ENST00000294702.6	TSL:2 MANE Select	c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-12_925-5delCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 174 AN: 138140 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000893

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00154

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000818

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0115 AC: 15786 AN: 1377086 Hom.: 4 AF XY: 0.0119 AC XY: 8132 AN XY: 684258

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00593 AC: 186 AN: 31370

American (AMR) AF: 0.0177 AC: 689 AN: 38968

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 578 AN: 24808

East Asian (EAS) AF: 0.00146 AC: 53 AN: 36402

South Asian (SAS) AF: 0.0130 AC: 1034 AN: 79266

European-Finnish (FIN) AF: 0.0105 AC: 502 AN: 47664

Middle Eastern (MID) AF: 0.0180 AC: 75 AN: 4162

European-Non Finnish (NFE) AF: 0.0113 AC: 11921 AN: 1057336

Other (OTH) AF: 0.0131 AC: 748 AN: 57110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00125 AC: 173 AN: 138250 Hom.: 0 Cov.: 0 AF XY: 0.00120 AC XY: 80 AN XY: 66426

African (AFR) AF: 0.00247 AC: 89 AN: 35966

American (AMR) AF: 0.000850 AC: 12 AN: 14116

Ashkenazi Jewish (ASJ) AF: 0.000893 AC: 3 AN: 3358

East Asian (EAS) AF: 0.000220 AC: 1 AN: 4536

South Asian (SAS) AF: 0.00129 AC: 5 AN: 3876

European-Finnish (FIN) AF: 0.00117 AC: 10 AN: 8564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000818 AC: 53 AN: 64788

Other (OTH) AF: 0.00 AC: 0 AN: 1932

Alfa AF: 0.00 Hom.: 437

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=91/9	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35896485; hg19: chr1-92944314;