1-92476036-A-G

Variant names:

• chr1-92476036-A-G
• NM_005263.5:c.1262T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005263.5(GFI1):​c.1262T>C​(p.Leu421Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L421F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1262T>C	p.Leu421Pro	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.1262T>C	p.Leu421Pro	missense_variant	Exon 7 of 7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1262T>C	p.Leu421Pro	missense_variant	Exon 7 of 7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1262T>C	p.Leu421Pro	missense_variant	Exon 7 of 7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.310T>C	p.Ser104Pro	missense_variant	Exon 2 of 2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L421P variant (also known as c.1262T>C), located in coding exon 6 of the GFI1 gene, results from a T to C substitution at nucleotide position 1262. The leucine at codon 421 is replaced by proline, an amino acid with 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;T;.
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.70
MutPred		0.40		Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);Loss of stability (P = 0.0079);
MVP		0.65
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.71

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: chr1-92941593;