NM_005263.5:c.1189G>A

Variant names:

• chr1-92476109-C-T
• rs747009263
• NM_005263.5:c.1189G>A

Variant summary

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

The NM_005263.5(GFI1):​c.1189G>A​(p.Gly397Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,720 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. G397V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1189G>A	p.Gly397Ser	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.1189G>A	p.Gly397Ser	missense_variant	Exon 7 of 7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1189G>A	p.Gly397Ser	missense_variant	Exon 7 of 7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1189G>A	p.Gly397Ser	missense_variant	Exon 7 of 7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.237G>A	p.Ser79Ser	synonymous_variant	Exon 2 of 2			ENSP00000512792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250896 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135632

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461720 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 397 of the GFI1 protein (p.Gly397Ser). This variant is present in population databases (rs747009263, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GFI1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	.;D;.
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.96	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.47
MutPred		0.21		Gain of disorder (P = 0.1223);Gain of disorder (P = 0.1223);Gain of disorder (P = 0.1223);
MVP		0.78
MPC		1.2
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.39

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: rs747009263; hg19: chr1-92941666; COSMIC: COSV99647443;