1-92476054-C-T

Position:

• chr1-92476054-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005263.5(GFI1):​c.1244G>A​(p.Arg415Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R415W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3507151).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1244G>A	p.Arg415Gln	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.1244G>A	p.Arg415Gln	missense_variant	7/7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1244G>A	p.Arg415Gln	missense_variant	7/7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1244G>A	p.Arg415Gln	missense_variant	7/7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.292G>A	p.Gly98Arg	missense_variant	2/2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250998 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 415 of the GFI1 protein (p.Arg415Gln). This variant is present in population databases (rs770564130, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GFI1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GFI1 protein function. 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	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.53
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	.;D;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.85	L;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.076	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.27
MutPred		0.41		Loss of MoRF binding (P = 0.0026);Loss of MoRF binding (P = 0.0026);Loss of MoRF binding (P = 0.0026);
MVP		0.70
MPC		1.7
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.47

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: rs770564130; hg19: chr1-92941611; COSMIC: COSV54042460;