dbSNP rs755193129: GFI1:p.Ile258Phe (chr1-92480615-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005263.5(GFI1):c.772A>T(p.Ile258Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. I258V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GFI1
NM_005263.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.271

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4041975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.772A>T	p.Ile258Phe	missense_variant	Exon 4 of 7	ENST00000294702.6	NP_005254.2	Q99684

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GFI1	ENST00000294702.6 link	c.772A>T	p.Ile258Phe	missense_variant	Exon 4 of 7	2	NM_005263.5	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5 link	c.772A>T	p.Ile258Phe	missense_variant	Exon 4 of 7	1		ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6 link	c.772A>T	p.Ile258Phe	missense_variant	Exon 4 of 7	1		ENSP00000399719.1	Q99684
GFI1	ENST00000696667.1 link	c.-130A>T		upstream_gene_variant				ENSP00000512792.1	A0A8Q3SIQ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412602

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699706

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:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Uncertain

0.53

D;D;D

Eigen

Benign

-0.0026

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

.;T;.

M_CAP

Benign

0.037

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.12

Sift

Benign

0.034

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.87

P;P;P

Vest4

0.24

MutPred

0.23

Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);

MVP

0.73

MPC

1.9

ClinPred

0.86

GERP RS

4.0

Varity_R

0.21

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over