rs775963992

chr9-132990980-T-Achr9-132990980-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

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 Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFI1B NM_001377304.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.09

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132990980-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 438347.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1B	NM_001377304.1	c.923T>A	p.Leu308Gln	missense_variant	7/7	ENST00000372122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1B	ENST00000372122.4	c.923T>A	p.Leu308Gln	missense_variant	7/7	1	NM_001377304.1	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251366 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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 SAS 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: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.36	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
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	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs775963992; hg19: chr9-135866367;