1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAGAG
• rs35896485
• NM_005263.5:c.925-10_925-5dupCTCTCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005263.5(GFI1):​c.925-10_925-5dupCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7892 hom., cov: 0)
  • Exomes 𝑓: 0.25 (1014 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• 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 -16 ACMG points.

• BP6: Variant 1-92478757-C-CAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAG is described in ClinVar as Benign. ClinVar VariationId is 1170883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 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.925-10_925-5dupCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-10_925-5dupCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-10_925-5dupCTCTCT		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_925-4insCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.323 AC: 44487 AN: 137834 Hom.: 7898 Cov.: 0

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.305

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.321

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.248 AC: 329767 AN: 1329534 Hom.: 1014 Cov.: 0 AF XY: 0.249 AC XY: 164605 AN XY: 660456

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

African (AFR) AF: 0.144 AC: 4377 AN: 30422

American (AMR) AF: 0.288 AC: 10729 AN: 37262

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5060 AN: 23910

East Asian (EAS) AF: 0.369 AC: 13052 AN: 35366

South Asian (SAS) AF: 0.316 AC: 24152 AN: 76492

European-Finnish (FIN) AF: 0.213 AC: 9805 AN: 46080

Middle Eastern (MID) AF: 0.250 AC: 1002 AN: 4002

European-Non Finnish (NFE) AF: 0.243 AC: 248079 AN: 1020988

Other (OTH) AF: 0.246 AC: 13511 AN: 55012

⚠️ 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: 0.323 AC: 44496 AN: 137940 Hom.: 7892 Cov.: 0 AF XY: 0.321 AC XY: 21288 AN XY: 66258

African (AFR) AF: 0.200 AC: 7159 AN: 35862

American (AMR) AF: 0.388 AC: 5467 AN: 14084

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1041 AN: 3350

East Asian (EAS) AF: 0.556 AC: 2517 AN: 4526

South Asian (SAS) AF: 0.518 AC: 2001 AN: 3866

European-Finnish (FIN) AF: 0.277 AC: 2365 AN: 8542

Middle Eastern (MID) AF: 0.305 AC: 83 AN: 272

European-Non Finnish (NFE) AF: 0.354 AC: 22879 AN: 64666

Other (OTH) AF: 0.319 AC: 615 AN: 1928

Alfa AF: 0.283 Hom.: 437

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	GFI1-related disorder (1)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant (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: COSV54041930; COSMIC: COSV54041930;