rs11164605

Positions:

• chr1-92480922-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005263.5(GFI1):​c.465C>T​(p.Cys155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,558,076 control chromosomes in the GnomAD database, including 527,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55359 hom., cov: 34)
  • Exomes 𝑓: 0.82 (472346 hom.)
• Consequence: GFI1 NM_005263.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.199

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-92480922-G-A is Benign according to our data. Variant chr1-92480922-G-A is described in ClinVar as [Benign]. Clinvar id is 211078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92480922-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.465C>T	p.Cys155=	synonymous_variant	4/7	ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.465C>T	p.Cys155=	synonymous_variant	4/7	2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.465C>T	p.Cys155=	synonymous_variant	4/7	1		P1
GFI1	ENST00000427103.6	c.465C>T	p.Cys155=	synonymous_variant	4/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129171 AN: 151846 Hom.: 55303 Cov.: 34

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.860

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.833

GnomAD3 exomes AF: 0.862 AC: 133337 AN: 154688 Hom.: 57823 AF XY: 0.865 AC XY: 72878 AN XY: 84290

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.909

Gnomad ASJ exome AF: 0.882

Gnomad EAS exome AF: 0.966

Gnomad SAS exome AF: 0.949

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.840

GnomAD4 exome AF: 0.818 AC: 1149886 AN: 1406116 Hom.: 472346 Cov.: 60 AF XY: 0.822 AC XY: 570637 AN XY: 694522

Gnomad4 AFR exome AF: 0.926

Gnomad4 AMR exome AF: 0.906

Gnomad4 ASJ exome AF: 0.883

Gnomad4 EAS exome AF: 0.975

Gnomad4 SAS exome AF: 0.950

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.841

GnomAD4 genome AF: 0.851 AC: 129287 AN: 151960 Hom.: 55359 Cov.: 34 AF XY: 0.853 AC XY: 63355 AN XY: 74272

Gnomad4 AFR AF: 0.923

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.887

Gnomad4 EAS AF: 0.969

Gnomad4 SAS AF: 0.952

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.799

Gnomad4 OTH AF: 0.836

Alfa AF: 0.819 Hom.: 18054

Bravo AF: 0.858

Asia WGS AF: 0.955 AC: 3318 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.2
DANN	Benign	0.91

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: rs11164605; hg19: chr1-92946479;