1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAG

Variant names:

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

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_925-5delCTCTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,516,400 control chromosomes in the GnomAD database, including 1,297 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (941 hom., cov: 0)
  • Exomes 𝑓: 0.11 (356 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign/Likely 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-CAGAGAG-C is Benign according to our data. Variant chr1-92478757-CAGAGAG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 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_925-5delCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-10_925-5delCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-10_925-5delCTCTCT		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.925-10_925-5delCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-10_925-5delCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-10_925-5delCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.111 AC: 15361 AN: 138130 Hom.: 941 Cov.: 0

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.0616

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.147

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.111 AC: 153606 AN: 1378160 Hom.: 356 AF XY: 0.111 AC XY: 76269 AN XY: 684712

African (AFR) AF: 0.0561 AC: 1759 AN: 31360

American (AMR) AF: 0.113 AC: 4423 AN: 38998

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4006 AN: 24908

East Asian (EAS) AF: 0.0172 AC: 627 AN: 36402

South Asian (SAS) AF: 0.0883 AC: 6998 AN: 79288

European-Finnish (FIN) AF: 0.107 AC: 5101 AN: 47656

Middle Eastern (MID) AF: 0.132 AC: 550 AN: 4170

European-Non Finnish (NFE) AF: 0.117 AC: 123468 AN: 1058230

Other (OTH) AF: 0.117 AC: 6674 AN: 57148

GnomAD4 genome AF: 0.111 AC: 15376 AN: 138240 Hom.: 941 Cov.: 0 AF XY: 0.113 AC XY: 7507 AN XY: 66424

African (AFR) AF: 0.0620 AC: 2231 AN: 35960

American (AMR) AF: 0.146 AC: 2057 AN: 14112

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 559 AN: 3354

East Asian (EAS) AF: 0.0254 AC: 115 AN: 4536

South Asian (SAS) AF: 0.111 AC: 430 AN: 3874

European-Finnish (FIN) AF: 0.126 AC: 1079 AN: 8582

Middle Eastern (MID) AF: 0.151 AC: 41 AN: 272

European-Non Finnish (NFE) AF: 0.132 AC: 8541 AN: 64776

Other (OTH) AF: 0.140 AC: 271 AN: 1930

Alfa AF: 0.141 Hom.: 437

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	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		=97/3	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;