dbSNP rs775963992: GFI1B:p.Leu308Gln (chr9-132990980-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001377304.1(GFI1B):c.923T>A(p.Leu308Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L308P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GFI1B
NM_001377304.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.09

Publications

3 publications found

Variant links:

Genes affected

GFI1B (HGNC:4238): (growth factor independent 1B transcriptional repressor) This gene encodes a zinc-finger containing transcriptional regulator that is primarily expressed in cells of hematopoietic lineage. The encoded protein complexes with numerous other transcriptional regulatory proteins including GATA-1, runt-related transcription factor 1 and histone deacetylases to control expression of genes involved in the development and maturation of erythrocytes and megakaryocytes. Mutations in this gene are the cause of the autosomal dominant platelet disorder, platelet-type bleeding disorder-17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

GFI1B Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 17
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
platelet storage pool deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GFI1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1B	NM_001377304.1 link	c.923T>A	p.Leu308Gln	missense_variant	Exon 7 of 7	ENST00000372122.4	NP_001364233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1B	ENST00000372122.4 link	c.923T>A	p.Leu308Gln	missense_variant	Exon 7 of 7	1	NM_001377304.1	ENSP00000361195.1		Q5VTD9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251366

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;T;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

.;D;D;T;T

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.53

D;D;D;D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.36

N;.;N;.;.

PhyloP100

5.1

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.9

D;.;D;D;.

REVEL

Benign

0.27

Sift

Uncertain

0.0050

D;.;D;D;.

Sift4G

Uncertain

0.011

D;.;D;D;.

Polyphen

0.99

D;.;D;D;.

Vest4

0.48

MutPred

0.35

Gain of disorder (P = 0.0524);.;Gain of disorder (P = 0.0524);.;.;

MVP

0.63

MPC

0.84

ClinPred

0.97

GERP RS

4.9

Varity_R

0.62

gMVP

0.38

Mutation Taster

=39/61

disease causing

(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