rs6666973

chr1-92480669-C-Gchr1-92480669-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005263.5(GFI1):c.718G>C(p.Glu240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,596,268 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (9 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.33

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008272231).
• BP6: Variant 1-92480669-C-G is Benign according to our data. Variant chr1-92480669-C-G is described in ClinVar as [Benign]. Clinvar id is 259705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00563 (857/152270) while in subpopulation AFR AF= 0.0182 (758/41574). AF 95% confidence interval is 0.0172. There are 8 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 853 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.718G>C	p.Glu240Gln	missense_variant	4/7	ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.718G>C	p.Glu240Gln	missense_variant	4/7	2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.718G>C	p.Glu240Gln	missense_variant	4/7	1		P1
GFI1	ENST00000427103.6	c.718G>C	p.Glu240Gln	missense_variant	4/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152154 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00118 AC: 257 AN: 217072 Hom.: 4 AF XY: 0.000927 AC XY: 112 AN XY: 120812

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.000745

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.000725

GnomAD4 exome AF: 0.000645 AC: 931 AN: 1443998 Hom.: 9 Cov.: 33 AF XY: 0.000535 AC XY: 384 AN XY: 718296

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000945

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000901

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.00563 AC: 857 AN: 152270 Hom.: 8 Cov.: 32 AF XY: 0.00556 AC XY: 414 AN XY: 74448

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.000844 Hom.: 0

Bravo AF: 0.00716

ESP6500AA AF: 0.0135 AC: 57

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00119 AC: 141

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GFI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.093	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.028	B;B;B
Vest4		0.15
MVP		0.62
MPC		0.63
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.094
gMVP		0.29

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: rs6666973; hg19: chr1-92946226;