1-92478757-CAGAGAGAGAGAGAGAGAGAGAGAG-CAGAGAGAGAGAGAGAGAGAGAGAGAG

Variant names:

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

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.925-6_925-5dupCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (949 hom., cov: 0)
  • Exomes 𝑓: 0.066 (53 hom.)
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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-C-CAG is Benign according to our data. Variant chr1-92478757-C-CAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 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_925-5dupCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-6_925-5dupCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-6_925-5dupCT		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_925-4insCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 13491 AN: 137960 Hom.: 948 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0142

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.0640

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0539

Gnomad OTH AF: 0.0912

GnomAD4 exome AF: 0.0659 AC: 88579 AN: 1344604 Hom.: 53 Cov.: 0 AF XY: 0.0661 AC XY: 44126 AN XY: 667500

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

African (AFR) AF: 0.172 AC: 5254 AN: 30634

American (AMR) AF: 0.0821 AC: 3085 AN: 37578

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 1459 AN: 24368

East Asian (EAS) AF: 0.125 AC: 4257 AN: 34126

South Asian (SAS) AF: 0.0792 AC: 6016 AN: 75968

European-Finnish (FIN) AF: 0.0584 AC: 2738 AN: 46872

Middle Eastern (MID) AF: 0.0651 AC: 265 AN: 4072

European-Non Finnish (NFE) AF: 0.0594 AC: 61486 AN: 1035160

Other (OTH) AF: 0.0720 AC: 4019 AN: 55826

⚠️ 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: 0.0978 AC: 13498 AN: 138066 Hom.: 949 Cov.: 0 AF XY: 0.0973 AC XY: 6451 AN XY: 66332

African (AFR) AF: 0.197 AC: 7069 AN: 35888

American (AMR) AF: 0.0943 AC: 1328 AN: 14078

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 210 AN: 3358

East Asian (EAS) AF: 0.0919 AC: 416 AN: 4526

South Asian (SAS) AF: 0.0573 AC: 222 AN: 3876

European-Finnish (FIN) AF: 0.0640 AC: 548 AN: 8556

Middle Eastern (MID) AF: 0.107 AC: 29 AN: 272

European-Non Finnish (NFE) AF: 0.0539 AC: 3487 AN: 64738

Other (OTH) AF: 0.0917 AC: 177 AN: 1930

Alfa AF: 0.114 Hom.: 437

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	GFI1-related disorder (1)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)
-	-	1	Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant (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;