rs34631763

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005263.5(GFI1):c.107G>A(p.Ser36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,602,830 control chromosomes in the GnomAD database, including 2,489 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S36L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.040 ( 183 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2306 hom. )

Consequence

GFI1
NM_005263.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.50

Publications

17 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=0.0018077791).

BP6

Variant 1-92483381-C-T is Benign according to our data. Variant chr1-92483381-C-T is described in ClinVar as Benign. ClinVar VariationId is 259699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.107G>A	p.Ser36Asn	missense_variant	Exon 2 of 7	ENST00000294702.6	NP_005254.2	Q99684

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6 link	c.107G>A	p.Ser36Asn	missense_variant	Exon 2 of 7	2	NM_005263.5	ENSP00000294702.5		Q99684

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6151

AN:

152242

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0430

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0585

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0592

Gnomad OTH

AF:

0.0431

GnomAD2 exomes

AF:

0.0397

AC:

9753

AN:

245864

AF XY:

0.0394

show subpopulations

Gnomad AFR exome

AF:

0.00945

Gnomad AMR exome

AF:

0.0282

Gnomad ASJ exome

AF:

0.0681

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0564

Gnomad OTH exome

AF:

0.0456

GnomAD4 exome

AF:

0.0521

AC:

75620

AN:

1450470

Hom.:

2306

Cov.:

AF XY:

0.0512

AC XY:

36943

AN XY:

722128

show subpopulations

African (AFR)

AF:

0.00743

AC:

247

AN:

33246

American (AMR)

AF:

0.0292

AC:

1305

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.0697

AC:

1814

AN:

26030

East Asian (EAS)

AF:

0.000101

AC:

AN:

39598

South Asian (SAS)

AF:

0.00977

AC:

839

AN:

85886

European-Finnish (FIN)

AF:

0.0559

AC:

2966

AN:

53056

Middle Eastern (MID)

AF:

0.0221

AC:

124

AN:

5616

European-Non Finnish (NFE)

AF:

0.0593

AC:

65322

AN:

1102460

Other (OTH)

AF:

0.0500

AC:

2999

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3604

7208

10813

14417

18021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2378

4756

7134

9512

11890

<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:

0.0404

AC:

6151

AN:

152360

Hom.:

183

Cov.:

AF XY:

0.0407

AC XY:

3030

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0102

AC:

426

AN:

41590

American (AMR)

AF:

0.0429

AC:

657

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0651

AC:

226

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0106

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0585

AC:

621

AN:

10624

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0592

AC:

4030

AN:

68030

Other (OTH)

AF:

0.0426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

303

606

910

1213

1516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0518

Hom.:

475

Bravo

AF:

0.0369

TwinsUK

AF:

0.0663

AC:

246

ALSPAC

AF:

0.0589

AC:

227

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.0545

AC:

469

ExAC

AF:

0.0377

AC:

4572

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0552

EpiControl

AF:

0.0552

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with congenital neutropaenia -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neutropenia, severe congenital, 2, autosomal dominant

Benign:1

Feb 02, 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

0.14

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.0087

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.45

.;T;.

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

2.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.94

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.063

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.026

B;B;B

Vest4

0.046

MPC

0.60

ClinPred

0.015

GERP RS

4.3

Varity_R

0.15

gMVP

0.062

Mutation Taster

=98/2

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