1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

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

Variant summary

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

The NM_005263.5(GFI1):​c.925-12_925-5dupCTCTCTCT 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 0.064 (392 hom., cov: 0)
  • Exomes 𝑓: 0.053 (200 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:6
• 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-CAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298180.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 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.925-12_925-5dupCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-12_925-5dupCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-12_925-5dupCTCTCTCT		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_925-4insCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 8882 AN: 138040 Hom.: 393 Cov.: 0

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.0320

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0685

Gnomad NFE AF: 0.0515

Gnomad OTH AF: 0.0514

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0531 AC: 72175 AN: 1358346 Hom.: 200 Cov.: 0 AF XY: 0.0531 AC XY: 35848 AN XY: 674840

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

African (AFR) AF: 0.0667 AC: 2049 AN: 30738

American (AMR) AF: 0.0529 AC: 2036 AN: 38502

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 1768 AN: 24238

East Asian (EAS) AF: 0.0744 AC: 2661 AN: 35770

South Asian (SAS) AF: 0.0621 AC: 4857 AN: 78164

European-Finnish (FIN) AF: 0.0562 AC: 2625 AN: 46698

Middle Eastern (MID) AF: 0.0574 AC: 236 AN: 4110

European-Non Finnish (NFE) AF: 0.0506 AC: 52799 AN: 1043802

Other (OTH) AF: 0.0558 AC: 3144 AN: 56324

⚠️ 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: 0.0643 AC: 8885 AN: 138150 Hom.: 392 Cov.: 0 AF XY: 0.0642 AC XY: 4265 AN XY: 66386

African (AFR) AF: 0.0807 AC: 2899 AN: 35918

American (AMR) AF: 0.0678 AC: 956 AN: 14092

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 289 AN: 3358

East Asian (EAS) AF: 0.124 AC: 560 AN: 4532

South Asian (SAS) AF: 0.0704 AC: 273 AN: 3876

European-Finnish (FIN) AF: 0.0495 AC: 424 AN: 8564

Middle Eastern (MID) AF: 0.0699 AC: 19 AN: 272

European-Non Finnish (NFE) AF: 0.0516 AC: 3339 AN: 64764

Other (OTH) AF: 0.0513 AC: 99 AN: 1930

Alfa AF: 0.0623 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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