1-92476103-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005263.5(GFI1):​c.1195G>C​(p.Asp399His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D399N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GFI1
NM_005263.5 missense

Scores

3
8
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.52
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GFI1NM_005263.5 linkc.1195G>C p.Asp399His missense_variant Exon 7 of 7 ENST00000294702.6 NP_005254.2 Q99684

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GFI1ENST00000294702.6 linkc.1195G>C p.Asp399His missense_variant Exon 7 of 7 2 NM_005263.5 ENSP00000294702.5 Q99684
GFI1ENST00000370332.5 linkc.1195G>C p.Asp399His missense_variant Exon 7 of 7 1 ENSP00000359357.1 Q99684
GFI1ENST00000427103.6 linkc.1195G>C p.Asp399His missense_variant Exon 7 of 7 1 ENSP00000399719.1 Q99684
GFI1ENST00000696667.1 linkc.243G>C p.Ala81Ala synonymous_variant Exon 2 of 2 ENSP00000512792.1 A0A8Q3SIQ6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461738
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727146
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.34
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
T;T;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
.;D;.
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;L
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.5
D;D;D
REVEL
Benign
0.25
Sift
Uncertain
0.0090
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.60
MutPred
0.29
Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);
MVP
0.77
MPC
1.8
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.45
gMVP
0.50

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: chr1-92941660; API