rs114487177

Variant names:

• chr1-92480480-G-A
• rs114487177
• NM_005263.5:c.792C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005263.5(GFI1):​c.792C>T​(p.Phe264Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,550,080 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: GFI1 NM_005263.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.28
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-92480480-G-A is Benign according to our data. Variant chr1-92480480-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BS2: High AC in GnomAd4 at 407 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.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	NP_005254.2
	GFI1	NM_001127215.3		c.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	NP_001120687.1
	GFI1	NM_001127216.3		c.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	NP_001120688.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	ENST00000294702.6	TSL:2 MANE Select	c.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	ENSP00000294702.5
	GFI1	ENST00000370332.5	TSL:1	c.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	ENSP00000359357.1
	GFI1	ENST00000427103.6	TSL:1	c.792C>T	p.Phe264Phe	synonymous	Exon 5 of 7	ENSP00000399719.1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 407 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00230 AC: 350 AN: 151934 AF XY: 0.00222

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.000828

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000263

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00368

GnomAD4 exome AF: 0.00373 AC: 5214 AN: 1397764 Hom.: 15 Cov.: 33 AF XY: 0.00366 AC XY: 2522 AN XY: 689466

African (AFR) AF: 0.000602 AC: 19 AN: 31572

American (AMR) AF: 0.00376 AC: 134 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.000636 AC: 16 AN: 25142

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35716

South Asian (SAS) AF: 0.000114 AC: 9 AN: 79212

European-Finnish (FIN) AF: 0.000394 AC: 19 AN: 48244

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5696

European-Non Finnish (NFE) AF: 0.00441 AC: 4757 AN: 1078556

Other (OTH) AF: 0.00435 AC: 252 AN: 57950

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74490

African (AFR) AF: 0.000722 AC: 30 AN: 41568

American (AMR) AF: 0.00438 AC: 67 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00361 Hom.: 1

Bravo AF: 0.00291

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		2.3
Mutation Taster		=99/1	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: rs114487177; hg19: chr1-92946037; COSMIC: COSV99647698; COSMIC: COSV99647698;