1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-CAGAGAGAGAG-C
• rs35896485
• NM_005263.5:c.925-14_925-5delCTCTCTCTCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005263.5(GFI1):​c.925-14_925-5delCTCTCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,519,596 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (13 hom., cov: 0)
  • Exomes 𝑓: 0.017 (16 hom.)
• 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
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 1-92478757-CAGAGAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAGAGAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298186.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0152 (2098/138278) while in subpopulation NFE AF = 0.0194 (1255/64796). AF 95% confidence interval is 0.0185. There are 13 homozygotes in GnomAd4. There are 996 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2098 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.925-14_925-5delCTCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-14_925-5delCTCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-14_925-5delCTCTCTCTCT		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.925-14_925-5delCTCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-14_925-5delCTCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-14_925-5delCTCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2098 AN: 138170 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00926

Gnomad AMI AF: 0.0142

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.00418

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0178

GnomAD4 exome AF: 0.0174 AC: 24029 AN: 1381318 Hom.: 16 AF XY: 0.0168 AC XY: 11510 AN XY: 686374

African (AFR) AF: 0.00831 AC: 261 AN: 31404

American (AMR) AF: 0.0133 AC: 521 AN: 39088

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 456 AN: 24950

East Asian (EAS) AF: 0.00275 AC: 100 AN: 36408

South Asian (SAS) AF: 0.00172 AC: 137 AN: 79448

European-Finnish (FIN) AF: 0.0165 AC: 788 AN: 47808

Middle Eastern (MID) AF: 0.0187 AC: 78 AN: 4176

European-Non Finnish (NFE) AF: 0.0196 AC: 20741 AN: 1060730

Other (OTH) AF: 0.0165 AC: 947 AN: 57306

GnomAD4 genome AF: 0.0152 AC: 2098 AN: 138278 Hom.: 13 Cov.: 0 AF XY: 0.0150 AC XY: 996 AN XY: 66442

African (AFR) AF: 0.00920 AC: 331 AN: 35966

American (AMR) AF: 0.0163 AC: 230 AN: 14118

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 80 AN: 3358

East Asian (EAS) AF: 0.00419 AC: 19 AN: 4536

South Asian (SAS) AF: 0.00103 AC: 4 AN: 3878

European-Finnish (FIN) AF: 0.0150 AC: 129 AN: 8578

Middle Eastern (MID) AF: 0.0147 AC: 4 AN: 272

European-Non Finnish (NFE) AF: 0.0194 AC: 1255 AN: 64796

Other (OTH) AF: 0.0176 AC: 34 AN: 1932

Alfa AF: 0.00 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	not provided (1)
-	1	-	Severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=84/16	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;