9-132986776-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377304.1(GFI1B):c.98C>G(p.Pro33Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFI1B NM_001377304.1 missense, splice_region
• Scores: Splicing: ADA: 0.009399
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16464368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1B	NM_001377304.1	c.98C>G	p.Pro33Arg	missense_variant, splice_region_variant	2/7	ENST00000372122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1B	ENST00000372122.4	c.98C>G	p.Pro33Arg	missense_variant, splice_region_variant	2/7	1	NM_001377304.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.98C>G (p.P33R) alteration is located in exon 2 (coding exon 1) of the GFI1B gene. This alteration results from a C to G substitution at nucleotide position 98, causing the proline (P) at amino acid position 33 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;.;N;N;.
REVEL	Benign	0.071
Sift	Benign	0.11	T;.;T;D;.
Sift4G	Uncertain	0.044	D;.;D;T;.
Polyphen		0.63	P;.;P;P;.
Vest4		0.27
MutPred		0.17		Loss of glycosylation at P28 (P = 0.1105);Loss of glycosylation at P28 (P = 0.1105);Loss of glycosylation at P28 (P = 0.1105);Loss of glycosylation at P28 (P = 0.1105);Loss of glycosylation at P28 (P = 0.1105);
MVP		0.39
MPC		0.34
ClinPred		0.39	T
GERP RS		4.4
Varity_R		0.040
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0094
dbscSNV1_RF	Benign	0.10
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135862163;