1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAG
• rs35896485
• NM_005263.5:c.925-8_925-5dupCTCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-8_925-5dupCTCT 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 0.054 (334 hom., cov: 0)
  • Exomes 𝑓: 0.11 (120 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-C-CAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298179.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.925-8_925-5dupCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-8_925-5dupCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-8_925-5dupCTCT		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_925-4insCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 7431 AN: 137984 Hom.: 333 Cov.: 0

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00711

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0143

Gnomad EAS AF: 0.0750

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.0342

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.111 AC: 147313 AN: 1327218 Hom.: 120 Cov.: 0 AF XY: 0.113 AC XY: 74432 AN XY: 659168

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

African (AFR) AF: 0.125 AC: 3825 AN: 30508

American (AMR) AF: 0.154 AC: 5769 AN: 37472

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 2078 AN: 23850

East Asian (EAS) AF: 0.232 AC: 8128 AN: 34980

South Asian (SAS) AF: 0.179 AC: 13580 AN: 75972

European-Finnish (FIN) AF: 0.0832 AC: 3832 AN: 46074

Middle Eastern (MID) AF: 0.114 AC: 459 AN: 4016

European-Non Finnish (NFE) AF: 0.101 AC: 103409 AN: 1019382

Other (OTH) AF: 0.113 AC: 6233 AN: 54964

⚠️ 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: 0.0539 AC: 7447 AN: 138092 Hom.: 334 Cov.: 0 AF XY: 0.0536 AC XY: 3555 AN XY: 66346

African (AFR) AF: 0.113 AC: 4061 AN: 35932

American (AMR) AF: 0.0369 AC: 520 AN: 14078

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 48 AN: 3356

East Asian (EAS) AF: 0.0747 AC: 338 AN: 4526

South Asian (SAS) AF: 0.0444 AC: 172 AN: 3876

European-Finnish (FIN) AF: 0.0196 AC: 167 AN: 8532

Middle Eastern (MID) AF: 0.0331 AC: 9 AN: 272

European-Non Finnish (NFE) AF: 0.0316 AC: 2046 AN: 64746

Other (OTH) AF: 0.0415 AC: 80 AN: 1930

Alfa AF: 0.101 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Neutropenia, severe congenital, 2, autosomal dominant (2)
-	-	2	not specified (2)
-	-	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		=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; COSMIC: COSV54043959; COSMIC: COSV54043959;