1-92476108-C-A

Position:

• chr1-92476108-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005263.5(GFI1):​c.1190G>T​(p.Gly397Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G397S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1190G>T	p.Gly397Val	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.1190G>T	p.Gly397Val	missense_variant	7/7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1190G>T	p.Gly397Val	missense_variant	7/7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1190G>T	p.Gly397Val	missense_variant	7/7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.238G>T	p.Ala80Ser	missense_variant	2/2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727152

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: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000413 Hom.: 0

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

Apr 11, 2022

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 397 of the GFI1 protein (p.Gly397Val). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	.;D;.
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-1.3	N;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.96	D;D;D
Vest4		0.49
MutPred		0.27		Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);
MVP		0.75
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.51

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: rs1657956373; hg19: chr1-92941665;