9-132986663-G-A

Position:

• chr9-132986663-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001377304.1(GFI1B):​c.-16G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,534,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GFI1B NM_001377304.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0400

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-132986663-G-A is Benign according to our data. Variant chr9-132986663-G-A is described in ClinVar as [Benign]. Clinvar id is 2581469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0014 (213/152262) while in subpopulation AFR AF= 0.00503 (209/41544). AF 95% confidence interval is 0.00447. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1B	NM_001377304.1	c.-16G>A		5_prime_UTR_variant	2/7	ENST00000372122.4	NP_001364233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1B	ENST00000372122	c.-16G>A		5_prime_UTR_variant	2/7	1	NM_001377304.1	ENSP00000361195.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000301 AC: 70 AN: 232884 Hom.: 0 AF XY: 0.000239 AC XY: 30 AN XY: 125536

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.0000911

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: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 171 AN: 1382450 Hom.: 0 Cov.: 24 AF XY: 0.000109 AC XY: 75 AN XY: 690396

Gnomad4 AFR exome AF: 0.00472

Gnomad4 AMR exome AF: 0.0000462

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: 0.00000383

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74444

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.00139

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 31, 2023

Variant summary: GFI1B c.-16G>A alters a non-conserved nucleotide and is located in the untranslated mRNA region upstream of the initiation codon. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 150916 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database and presence of a homozygous individual strongly suggest that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.-16G>A in individuals affected with Platelet-Type Bleeding Disorder 17 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.3
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs201670238; hg19: chr9-135862050;