chr1-92476037-G-A

Variant names:

• chr1-92476037-G-A
• NM_005263.5:c.1261C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005263.5(GFI1):​c.1261C>T​(p.Leu421Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1261C>T	p.Leu421Phe	missense_variant	Exon 7 of 7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.1261C>T	p.Leu421Phe	missense_variant	Exon 7 of 7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1261C>T	p.Leu421Phe	missense_variant	Exon 7 of 7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1261C>T	p.Leu421Phe	missense_variant	Exon 7 of 7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.309C>T	p.Gly103Gly	synonymous_variant	Exon 2 of 2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L421F variant (also known as c.1261C>T), located in coding exon 6 of the GFI1 gene, results from a C to T substitution at nucleotide position 1261. The leucine at codon 421 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 421 of the GFI1 protein (p.Leu421Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GFI1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	.;D;.
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.21
Sift	Benign	0.059	T;T;T
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.53
MutPred		0.36		Loss of catalytic residue at L421 (P = 0.033);Loss of catalytic residue at L421 (P = 0.033);Loss of catalytic residue at L421 (P = 0.033);
MVP		0.73
MPC		1.6
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.25
gMVP		0.33

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: chr1-92941594;