1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005263.5(GFI1):​c.925-14_925-5dupCTCTCTCTCT 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 0.066 (405 hom., cov: 0)
  • Exomes 𝑓: 0.038 (137 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:4
• 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-C-CAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298183.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

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_925-5dupCTCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-14_925-5dupCTCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-14_925-5dupCTCTCTCTCT		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.925-5_925-4insCTCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 9102 AN: 137926 Hom.: 402 Cov.: 0

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0582

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.0608

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0383 AC: 52045 AN: 1357718 Hom.: 137 Cov.: 0 AF XY: 0.0382 AC XY: 25735 AN XY: 674012

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

African (AFR) AF: 0.0280 AC: 866 AN: 30894

American (AMR) AF: 0.0198 AC: 765 AN: 38584

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1329 AN: 24368

East Asian (EAS) AF: 0.0236 AC: 850 AN: 35992

South Asian (SAS) AF: 0.0355 AC: 2762 AN: 77770

European-Finnish (FIN) AF: 0.0686 AC: 3193 AN: 46570

Middle Eastern (MID) AF: 0.0357 AC: 146 AN: 4084

European-Non Finnish (NFE) AF: 0.0384 AC: 40022 AN: 1043168

Other (OTH) AF: 0.0375 AC: 2112 AN: 56288

⚠️ 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: 0.0660 AC: 9108 AN: 138036 Hom.: 405 Cov.: 0 AF XY: 0.0681 AC XY: 4517 AN XY: 66300

African (AFR) AF: 0.0426 AC: 1529 AN: 35918

American (AMR) AF: 0.0415 AC: 585 AN: 14100

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 390 AN: 3354

East Asian (EAS) AF: 0.0581 AC: 263 AN: 4530

South Asian (SAS) AF: 0.0555 AC: 215 AN: 3876

European-Finnish (FIN) AF: 0.124 AC: 1059 AN: 8508

Middle Eastern (MID) AF: 0.0551 AC: 15 AN: 272

European-Non Finnish (NFE) AF: 0.0743 AC: 4807 AN: 64704

Other (OTH) AF: 0.0632 AC: 122 AN: 1930

Alfa AF: 0.0369 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	GFI1-related disorder (1)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

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;