1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-C-CAGAGAGAGAGAGAGAG
• rs35896485
• NM_005263.5:c.925-20_925-5dupCTCTCTCTCTCTCTCT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005263.5(GFI1):​c.925-20_925-5dupCTCTCTCTCTCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (7 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:2
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 1-92478757-C-CAGAGAGAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAGAGAGAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538141.
• BS2: High AC in GnomAd4 at 489 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.925-20_925-5dupCTCTCTCTCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-20_925-5dupCTCTCTCTCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-20_925-5dupCTCTCTCTCTCTCTCT		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_925-4insCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 488 AN: 138140 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00156

Gnomad ASJ AF: 0.00268

Gnomad EAS AF: 0.000880

Gnomad SAS AF: 0.00257

Gnomad FIN AF: 0.00128

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00164 AC: 2264 AN: 1381224 Hom.: 7 Cov.: 0 AF XY: 0.00161 AC XY: 1103 AN XY: 686270

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

African (AFR) AF: 0.00338 AC: 106 AN: 31344

American (AMR) AF: 0.000767 AC: 30 AN: 39110

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 26 AN: 24972

East Asian (EAS) AF: 0.000605 AC: 22 AN: 36388

South Asian (SAS) AF: 0.00156 AC: 124 AN: 79366

European-Finnish (FIN) AF: 0.000815 AC: 39 AN: 47844

Middle Eastern (MID) AF: 0.00168 AC: 7 AN: 4172

European-Non Finnish (NFE) AF: 0.00170 AC: 1804 AN: 1060742

Other (OTH) AF: 0.00185 AC: 106 AN: 57286

⚠️ 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: 0.00354 AC: 489 AN: 138250 Hom.: 4 Cov.: 0 AF XY: 0.00322 AC XY: 214 AN XY: 66424

African (AFR) AF: 0.00540 AC: 194 AN: 35950

American (AMR) AF: 0.00156 AC: 22 AN: 14116

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 9 AN: 3358

East Asian (EAS) AF: 0.000882 AC: 4 AN: 4536

South Asian (SAS) AF: 0.00258 AC: 10 AN: 3878

European-Finnish (FIN) AF: 0.00128 AC: 11 AN: 8584

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

European-Non Finnish (NFE) AF: 0.00357 AC: 231 AN: 64780

Other (OTH) AF: 0.00207 AC: 4 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
-	-	1	GFI1-related disorder (1)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=100/0	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;