Genetic Variant NM_005263.5:c.299-493T>G (chr1-92481581-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005263.5(GFI1):c.299-493T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 152,086 control chromosomes in the GnomAD database, including 39,714 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.72 ( 39714 hom., cov: 32)

Consequence

GFI1
NM_005263.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.933

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1	NM_005263.5 link	c.299-493T>G		intron_variant	Intron 3 of 6	ENST00000294702.6	NP_005254.2	Q99684

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GFI1	ENST00000294702.6 link	c.299-493T>G	intron_variant	Intron 3 of 6	2	NM_005263.5	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5 link	c.299-493T>G	intron_variant	Intron 3 of 6	1		ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6 link	c.299-493T>G	intron_variant	Intron 3 of 6	1		ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108767

AN:

151968

Hom.:

39668

Cov.:

show subpopulations

Gnomad AFR

AF:

0.818

Gnomad AMI

AF:

0.738

Gnomad AMR

AF:

0.704

Gnomad ASJ

AF:

0.685

Gnomad EAS

AF:

0.945

Gnomad SAS

AF:

0.849

Gnomad FIN

AF:

0.627

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.645

Gnomad OTH

AF:

0.671

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.716

AC:

108873

AN:

152086

Hom.:

39714

Cov.:

AF XY:

0.718

AC XY:

53372

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.818

AC:

33954

AN:

41492

American (AMR)

AF:

0.705

AC:

10778

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

2377

AN:

3470

East Asian (EAS)

AF:

0.945

AC:

4880

AN:

5164

South Asian (SAS)

AF:

0.849

AC:

4095

AN:

4826

European-Finnish (FIN)

AF:

0.627

AC:

6626

AN:

10560

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.645

AC:

43863

AN:

67956

Other (OTH)

AF:

0.675

AC:

1426

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1571

3141

4712

6282

7853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.668

Hom.:

12865

Bravo

AF:

0.725

Asia WGS

AF:

0.883

AC:

3069

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.9

(source)

DANN

Benign

0.46

PhyloP100

-0.93

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over