1-92476109-C-T

Position:

chr1-92476109-C-T

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
GFI1	NM_005263.5 linkuse as main transcript	c.1189G>A	p.Gly397Ser	missense_variant	7/7	ENST00000294702.6	NP_005254.2	Q99684

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GFI1	ENST00000294702.6 linkuse as main transcript	c.1189G>A	p.Gly397Ser	missense_variant	7/7	2	NM_005263.5	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5 linkuse as main transcript	c.1189G>A	p.Gly397Ser	missense_variant	7/7	1		ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6 linkuse as main transcript	c.1189G>A	p.Gly397Ser	missense_variant	7/7	1		ENSP00000399719.1	Q99684
GFI1	ENST00000696667.1 linkuse as main transcript	c.237G>A	p.Ser79Ser	synonymous_variant	2/2			ENSP00000512792.1	A0A8Q3SIQ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250896

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135632

show subpopulations

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:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727142

show subpopulations

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.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neutropenia, severe congenital, 2, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2022

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. 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. This variant has not been reported in the literature in individuals affected with GFI1-related conditions. This variant is present in population databases (rs747009263, gnomAD 0.004%). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

CADD

Pathogenic

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

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.96

N;N;N

PrimateAI

Pathogenic

0.88

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over