1-92478631-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_005263.5(GFI1):​c.1047C>G​(p.Phe349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F349F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

GFI1
NM_005263.5 missense

Scores

5
9
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.92
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.887
BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GFI1NM_005263.5 linkc.1047C>G p.Phe349Leu missense_variant Exon 6 of 7 ENST00000294702.6 NP_005254.2 Q99684

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GFI1ENST00000294702.6 linkc.1047C>G p.Phe349Leu missense_variant Exon 6 of 7 2 NM_005263.5 ENSP00000294702.5 Q99684
GFI1ENST00000370332.5 linkc.1047C>G p.Phe349Leu missense_variant Exon 6 of 7 1 ENSP00000359357.1 Q99684
GFI1ENST00000427103.6 linkc.1047C>G p.Phe349Leu missense_variant Exon 6 of 7 1 ENSP00000399719.1 Q99684
GFI1ENST00000696667.1 linkc.138+1717C>G intron_variant Intron 1 of 1 ENSP00000512792.1 A0A8Q3SIQ6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461854
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;D;D
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.89
.;D;.
M_CAP
Benign
0.040
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
2.0
M;M;M
PrimateAI
Pathogenic
0.97
D
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.60
P;P;P
Vest4
0.94
MutPred
0.73
Gain of catalytic residue at F349 (P = 0.0293);Gain of catalytic residue at F349 (P = 0.0293);Gain of catalytic residue at F349 (P = 0.0293);
MVP
0.83
MPC
1.8
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.85
gMVP
0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-92944188; API