NM_005263.5:c.1047C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005263.5(GFI1):c.1047C>T(p.Phe349Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0196 in 1,613,968 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.020 ( 343 hom. )

Consequence

GFI1
NM_005263.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.92

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 1-92478631-G-A is Benign according to our data. Variant chr1-92478631-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2010/152170) while in subpopulation NFE AF = 0.0212 (1442/68004). AF 95% confidence interval is 0.0203. There are 25 homozygotes in GnomAd4. There are 960 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2010 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.1047C>T	p.Phe349Phe	synonymous_variant	Exon 6 of 7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GFI1	ENST00000294702.6 link	c.1047C>T	p.Phe349Phe	synonymous_variant	Exon 6 of 7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5 link	c.1047C>T	p.Phe349Phe	synonymous_variant	Exon 6 of 7	1		ENSP00000359357.1
GFI1	ENST00000427103.6 link	c.1047C>T	p.Phe349Phe	synonymous_variant	Exon 6 of 7	1		ENSP00000399719.1
GFI1	ENST00000696667.1 link	c.138+1717C>T		intron_variant	Intron 1 of 1			ENSP00000512792.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2011

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00989

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0137

AC:

3451

AN:

251492

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0173

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0203

AC:

29670

AN:

1461798

Hom.:

343

Cov.:

AF XY:

0.0200

AC XY:

14545

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00305

AC:

102

AN:

33478

American (AMR)

AF:

0.00615

AC:

275

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00673

AC:

176

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0110

AC:

951

AN:

86256

European-Finnish (FIN)

AF:

0.0171

AC:

912

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0234

AC:

26059

AN:

1111930

Other (OTH)

AF:

0.0195

AC:

1180

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1468

2935

4403

5870

7338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

958

1916

2874

3832

4790

<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:

0.0132

AC:

2010

AN:

152170

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

960

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00378

AC:

157

AN:

41506

American (AMR)

AF:

0.00988

AC:

151

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.0118

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0143

AC:

152

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1442

AN:

68004

Other (OTH)

AF:

0.0114

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

182

274

365

456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0179

Hom.:

Bravo

AF:

0.0128

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0197

EpiControl

AF:

0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GFI1-related disorder

Benign:1

Aug 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

4.9

Mutation Taster

=95/5

polymorphism (auto)

(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