rs114487177

chr1-92480480-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005263.5(GFI1):c.792C>T(p.Phe264=) 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:6
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 298188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92480480-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BS2: High AC in GnomAd at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.792C>T	p.Phe264=	synonymous_variant	5/7	ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.792C>T	p.Phe264=	synonymous_variant	5/7	2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.792C>T	p.Phe264=	synonymous_variant	5/7	1		P1
GFI1	ENST00000427103.6	c.792C>T	p.Phe264=	synonymous_variant	5/7	1		P1
GFI1	ENST00000696667.1	c.6C>T	p.Phe2=	synonymous_variant	1/2

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

GnomAD3 exomes AF: 0.00230 AC: 350 AN: 151934 Hom.: 0 AF XY: 0.00222 AC XY: 179 AN XY: 80798

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 SAS exome AF: 0.0000879

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

Gnomad4 AFR exome AF: 0.000602

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.000636

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.000394

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00435

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

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00434

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00361 Hom.: 1

Bravo AF: 0.00291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	GFI1: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 01, 2021

- -

Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Benign	0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs114487177; hg19: chr1-92946037; COSMIC: COSV99647698; COSMIC: COSV99647698;