1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAG

Variant names:

• chr1-92478757-CAG-C
• rs35896485
• NM_005263.5:c.925-6_925-5delCT

Variant summary

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

The NM_005263.5(GFI1):​c.925-6_925-5delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,507,098 control chromosomes in the GnomAD database, including 1,344 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1084 hom., cov: 0)
  • Exomes 𝑓: 0.12 (260 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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-CAG-C is Benign according to our data. Variant chr1-92478757-CAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298182.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 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.925-6_925-5delCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-6_925-5delCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-6_925-5delCT		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.925-6_925-5delCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-6_925-5delCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-6_925-5delCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.123 AC: 17031 AN: 138020 Hom.: 1087 Cov.: 0

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0301

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.117 AC: 160236 AN: 1368968 Hom.: 260 AF XY: 0.115 AC XY: 78131 AN XY: 680242

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

African (AFR) AF: 0.110 AC: 3416 AN: 31062

American (AMR) AF: 0.0644 AC: 2494 AN: 38720

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2604 AN: 24658

East Asian (EAS) AF: 0.0255 AC: 924 AN: 36262

South Asian (SAS) AF: 0.0439 AC: 3465 AN: 78988

European-Finnish (FIN) AF: 0.137 AC: 6454 AN: 47168

Middle Eastern (MID) AF: 0.102 AC: 421 AN: 4146

European-Non Finnish (NFE) AF: 0.128 AC: 134305 AN: 1051216

Other (OTH) AF: 0.108 AC: 6153 AN: 56748

⚠️ 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: 0.123 AC: 17049 AN: 138130 Hom.: 1084 Cov.: 0 AF XY: 0.122 AC XY: 8126 AN XY: 66374

African (AFR) AF: 0.114 AC: 4091 AN: 35926

American (AMR) AF: 0.101 AC: 1421 AN: 14104

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 428 AN: 3356

East Asian (EAS) AF: 0.0302 AC: 137 AN: 4534

South Asian (SAS) AF: 0.0423 AC: 164 AN: 3874

European-Finnish (FIN) AF: 0.164 AC: 1407 AN: 8568

Middle Eastern (MID) AF: 0.121 AC: 33 AN: 272

European-Non Finnish (NFE) AF: 0.138 AC: 8956 AN: 64722

Other (OTH) AF: 0.133 AC: 257 AN: 1930

Alfa AF: 0.133 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35896485; hg19: chr1-92944314;