rs143708376

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005263.5(GFI1):c.1198C>T(p.Leu400Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,614,136 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L400L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 7 hom. )

Consequence

GFI1
NM_005263.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.67

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

neutropenia, severe congenital, 2, autosomal dominant
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
severe congenital neutropenia
Inheritance: AD Classification: MODERATE Submitted by: Illumina
autosomal dominant severe congenital neutropenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GFI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011156172).

BP6

Variant 1-92476100-G-A is Benign according to our data. Variant chr1-92476100-G-A is described in ClinVar as Benign. ClinVar VariationId is 470694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00468 (713/152366) while in subpopulation AFR AF = 0.0164 (682/41582). AF 95% confidence interval is 0.0154. There are 4 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 713 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.1198C>T	p.Leu400Phe	missense_variant	Exon 7 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.1198C>T	p.Leu400Phe	missense_variant	Exon 7 of 7	2	NM_005263.5	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5 link	c.1198C>T	p.Leu400Phe	missense_variant	Exon 7 of 7	1		ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6 link	c.1198C>T	p.Leu400Phe	missense_variant	Exon 7 of 7	1		ENSP00000399719.1	Q99684
GFI1	ENST00000696667.1 link	c.246C>T	p.Thr82Thr	synonymous_variant	Exon 2 of 2			ENSP00000512792.1	A0A8Q3SIQ6

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

700

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00103

AC:

258

AN:

250976

AF XY:

0.000693

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000441

AC:

644

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0168

AC:

564

AN:

33480

American (AMR)

AF:

0.000604

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111970

Other (OTH)

AF:

0.000695

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00468

AC:

713

AN:

152366

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0164

AC:

682

AN:

41582

American (AMR)

AF:

0.00124

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68044

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.00513

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00125

AC:

152

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 22, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neutropenia, severe congenital, 2, autosomal dominant

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-0.065

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

.;D;.

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

N;N;N

PhyloP100

4.7

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.88

P;P;P

Vest4

0.63

MVP

0.58

MPC

1.7

ClinPred

0.039

GERP RS

3.7

Varity_R

0.31

gMVP

0.37

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over