1-92476111-A-C

Position:

• chr1-92476111-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005263.5(GFI1):​c.1187T>G​(p.Phe396Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F396F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1187T>G	p.Phe396Cys	missense_variant	7/7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.1187T>G	p.Phe396Cys	missense_variant	7/7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1187T>G	p.Phe396Cys	missense_variant	7/7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1187T>G	p.Phe396Cys	missense_variant	7/7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.235T>G	p.Ser79Ala	missense_variant	2/2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2024

The p.F396C variant (also known as c.1187T>G), located in coding exon 6 of the GFI1 gene, results from a T to G substitution at nucleotide position 1187. The phenylalanine at codon 396 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.66		Gain of disorder (P = 0.0727);Gain of disorder (P = 0.0727);Gain of disorder (P = 0.0727);
MVP		0.77
MPC		2.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-92941668;