rs114487177

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005263.5(GFI1):c.792C>T(p.Phe264Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,550,080 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

GFI1
NM_005263.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.28

Publications

4 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 1-92480480-G-A is Benign according to our data. Variant chr1-92480480-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 298188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.28 with no splicing effect.

BS2

High AC in GnomAd4 at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.792C>T	p.Phe264Phe	synonymous_variant	Exon 5 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.792C>T	p.Phe264Phe	synonymous_variant	Exon 5 of 7	2	NM_005263.5	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5 link	c.792C>T	p.Phe264Phe	synonymous_variant	Exon 5 of 7	1		ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6 link	c.792C>T	p.Phe264Phe	synonymous_variant	Exon 5 of 7	1		ENSP00000399719.1	Q99684
GFI1	ENST00000696667.1 link	c.6C>T	p.Phe2Phe	synonymous_variant	Exon 1 of 2			ENSP00000512792.1	A0A8Q3SIQ6

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

407

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00230

AC:

350

AN:

151934

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.00373

Gnomad ASJ exome

AF:

0.000828

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000263

Gnomad NFE exome

AF:

0.00389

Gnomad OTH exome

AF:

0.00368

GnomAD4 exome

AF:

0.00373

AC:

5214

AN:

1397764

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2522

AN XY:

689466

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

31572

American (AMR)

AF:

0.00376

AC:

134

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.000636

AC:

AN:

25142

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35716

South Asian (SAS)

AF:

0.000114

AC:

AN:

79212

European-Finnish (FIN)

AF:

0.000394

AC:

AN:

48244

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00441

AC:

4757

AN:

1078556

Other (OTH)

AF:

0.00435

AC:

252

AN:

57950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

322

645

967

1290

1612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.00267

AC:

407

AN:

152316

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41568

American (AMR)

AF:

0.00438

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00434

AC:

295

AN:

68022

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

112

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:

0.00361

Hom.:

Bravo

AF:

0.00291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFI1: BP4, BP7, BS2 -

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Oct 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Oct 01, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neutropenia, severe congenital, 2, autosomal dominant

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonimmune chronic idiopathic neutropenia of adults;C2751288:Neutropenia, severe congenital, 2, autosomal dominant

Benign:1

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.3

Mutation Taster

=99/1

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