rs533176227

Variant names:

• chr1-92480956-G-A
• rs533176227
• NM_005263.5:c.431C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-92480956-G-A
• chr1-92480956-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005263.5(GFI1):​c.431C>T​(p.Ala144Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. A144G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

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]

GFI1 Gene-Disease associations (from GenCC):

• neutropenia, severe congenital, 2, autosomal dominant

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• severe congenital neutropenia

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20932999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.431C>T	p.Ala144Val	missense_variant	Exon 4 of 7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.431C>T	p.Ala144Val	missense_variant	Exon 4 of 7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.431C>T	p.Ala144Val	missense_variant	Exon 4 of 7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.431C>T	p.Ala144Val	missense_variant	Exon 4 of 7	1		ENSP00000399719.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439078 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 714056

African (AFR) AF: 0.00 AC: 0 AN: 32958

American (AMR) AF: 0.00 AC: 0 AN: 41330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 38452

South Asian (SAS) AF: 0.00 AC: 0 AN: 83258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101870

Other (OTH) AF: 0.0000168 AC: 1 AN: 59496

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A144V variant (also known as c.431C>T), located in coding exon 3 of the GFI1 gene, results from a C to T substitution at nucleotide position 431. The alanine at codon 144 is replaced by valine, 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	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	.;T;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.091
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.26
MutPred		0.35		Gain of catalytic residue at A144 (P = 0.0339);Gain of catalytic residue at A144 (P = 0.0339);Gain of catalytic residue at A144 (P = 0.0339);
MVP		0.78
MPC		0.65
ClinPred		0.51	D
GERP RS		3.1
Varity_R		0.11
gMVP		0.31
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs533176227; hg19: chr1-92946513;