1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_005263.5(GFI1):​c.925-8_925-5delCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,373,978 control chromosomes in the GnomAD database, including 16 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.018 (21 hom., cov: 0)
  • Exomes 𝑓: 0.032 (16 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:3
• 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 -1 ACMG points.

• BP6: Variant 1-92478757-CAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298184.

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_925-5delCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-8_925-5delCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-8_925-5delCTCT		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.925-8_925-5delCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-8_925-5delCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-8_925-5delCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2493 AN: 138140 Hom.: 21 Cov.: 0

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00572

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0171

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0194

GnomAD4 exome AF: 0.0320 AC: 43945 AN: 1373978 Hom.: 16 AF XY: 0.0316 AC XY: 21584 AN XY: 682668

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

African (AFR) AF: 0.0383 AC: 1197 AN: 31240

American (AMR) AF: 0.0165 AC: 643 AN: 38968

Ashkenazi Jewish (ASJ) AF: 0.0356 AC: 885 AN: 24840

East Asian (EAS) AF: 0.00636 AC: 231 AN: 36348

South Asian (SAS) AF: 0.0179 AC: 1418 AN: 79276

European-Finnish (FIN) AF: 0.0355 AC: 1687 AN: 47456

Middle Eastern (MID) AF: 0.0240 AC: 100 AN: 4166

European-Non Finnish (NFE) AF: 0.0341 AC: 35943 AN: 1054668

Other (OTH) AF: 0.0323 AC: 1841 AN: 57016

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0181 AC: 2497 AN: 138248 Hom.: 21 Cov.: 0 AF XY: 0.0185 AC XY: 1228 AN XY: 66428

African (AFR) AF: 0.0262 AC: 943 AN: 35960

American (AMR) AF: 0.0106 AC: 149 AN: 14116

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 62 AN: 3358

East Asian (EAS) AF: 0.00573 AC: 26 AN: 4536

South Asian (SAS) AF: 0.0157 AC: 61 AN: 3876

European-Finnish (FIN) AF: 0.0162 AC: 139 AN: 8574

Middle Eastern (MID) AF: 0.0184 AC: 5 AN: 272

European-Non Finnish (NFE) AF: 0.0166 AC: 1075 AN: 64782

Other (OTH) AF: 0.0192 AC: 37 AN: 1930

Alfa AF: 0.00 Hom.: 437

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	not specified (1)
-	1	-	Severe congenital neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=91/9	polymorphism

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;