dbSNP rs143913803: GFI1:p.Ser56Ser (chr1-92482994-G-A) – ACMG Classification: Benign (-17 pts)

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.168C>T(p.Ser56Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,610,104 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 25 hom. )

Consequence

GFI1
NM_005263.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.451

Publications

2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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=-0.47).

BP6

Variant 1-92482994-G-A is Benign according to our data. Variant chr1-92482994-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.451 with no splicing effect.

BS2

High AC in GnomAd4 at 535 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005263.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFI1	NM_005263.5	MANE Select	c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	NP_005254.2	Q99684
GFI1	NM_001127215.3		c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	NP_001120687.1	Q99684
GFI1	NM_001127216.3		c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	NP_001120688.1	Q99684

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFI1	ENST00000294702.6	TSL:2 MANE Select	c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	ENSP00000294702.5	Q99684
GFI1	ENST00000370332.5	TSL:1	c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	ENSP00000359357.1	Q99684
GFI1	ENST00000427103.6	TSL:1	c.168C>T	p.Ser56Ser	synonymous	Exon 3 of 7	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes

AF:

0.00351

AC:

535

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00634

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00529

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00252

AC:

628

AN:

249016

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000625

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000729

Gnomad NFE exome

AF:

0.00400

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00498

AC:

7258

AN:

1457772

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

3505

AN XY:

724658

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

33368

American (AMR)

AF:

0.00278

AC:

124

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00132

AC:

114

AN:

86212

European-Finnish (FIN)

AF:

0.000918

AC:

AN:

52264

Middle Eastern (MID)

AF:

0.000881

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00602

AC:

6675

AN:

1109708

Other (OTH)

AF:

0.00434

AC:

261

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

371

741

1112

1482

1853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.00351

AC:

535

AN:

152332

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

258

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41578

American (AMR)

AF:

0.00633

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00529

AC:

360

AN:

68028

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

117

146

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:

0.00350

Hom.:

Bravo

AF:

0.00388

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00373

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Neutropenia, severe congenital, 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

0.45

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over