NM_005263.5:c.925-22_925-5dupCTCTCTCTCTCTCTCTCT

Variant names:

• chr1-92478757-C-CAGAGAGAGAGAGAGAGAG
• rs35896485
• NM_005263.5:c.925-22_925-5dupCTCTCTCTCTCTCTCTCT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_005263.5(GFI1):​c.925-22_925-5dupCTCTCTCTCTCTCTCTCT 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFI1 NM_005263.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B: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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-92478757-C-CAGAGAGAGAGAGAGAGAG is Benign according to our data. Variant chr1-92478757-C-CAGAGAGAGAGAGAGAGAG is described in ClinVar as Benign. ClinVar VariationId is 788327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 214 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.925-22_925-5dupCTCTCTCTCTCTCTCTCT		splice_region intron	N/A	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.925-22_925-5dupCTCTCTCTCTCTCTCTCT		splice_region intron	N/A	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.925-22_925-5dupCTCTCTCTCTCTCTCTCT		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_925-4insCTCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.925-5_925-4insCTCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.925-5_925-4insCTCTCTCTCTCTCTCTCT		splice_region intron	N/A	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 213 AN: 138164 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00118

Gnomad AMR AF: 0.000709

Gnomad ASJ AF: 0.000596

Gnomad EAS AF: 0.000660

Gnomad SAS AF: 0.000257

Gnomad FIN AF: 0.000233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000494

Gnomad OTH AF: 0.00209

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000245 AC: 338 AN: 1382350 Hom.: 1 Cov.: 0 AF XY: 0.000247 AC XY: 170 AN XY: 686876

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

African (AFR) AF: 0.00230 AC: 72 AN: 31366

American (AMR) AF: 0.000383 AC: 15 AN: 39114

Ashkenazi Jewish (ASJ) AF: 0.000160 AC: 4 AN: 24996

East Asian (EAS) AF: 0.000357 AC: 13 AN: 36398

South Asian (SAS) AF: 0.000277 AC: 22 AN: 79490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4180

European-Non Finnish (NFE) AF: 0.000184 AC: 195 AN: 1061610

Other (OTH) AF: 0.000296 AC: 17 AN: 57340

⚠️ 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: 0.00155 AC: 214 AN: 138272 Hom.: 0 Cov.: 0 AF XY: 0.00146 AC XY: 97 AN XY: 66442

African (AFR) AF: 0.00442 AC: 159 AN: 35952

American (AMR) AF: 0.000708 AC: 10 AN: 14118

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 2 AN: 3358

East Asian (EAS) AF: 0.000661 AC: 3 AN: 4536

South Asian (SAS) AF: 0.000258 AC: 1 AN: 3878

European-Finnish (FIN) AF: 0.000233 AC: 2 AN: 8584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000494 AC: 32 AN: 64798

Other (OTH) AF: 0.00207 AC: 4 AN: 1932

Alfa AF: 0.00 Hom.: 437

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	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;