rs11243940

Variant names:

• chr9-132945985-A-G
• rs11243940
• ENST00000339463.7:c.-701+316A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000339463.7(GFI1B):​c.-701+316A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,024 control chromosomes in the GnomAD database, including 3,753 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3753 hom., cov: 31)
• Consequence: GFI1B ENST00000339463.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 8 publications found

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]

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

MIR548AW (HGNC:43454): (microRNA 548aw) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1B	NM_004188.8	c.-701+316A>G		intron_variant	Intron 1 of 10		NP_004179.3
MIR548AW	NR_049862.1	n.*214A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1B	ENST00000339463.7	c.-701+316A>G		intron_variant	Intron 1 of 10	1		ENSP00000344782.3
TSC1	ENST00000643362.2	c.-144+774T>C		intron_variant	Intron 1 of 19			ENSP00000496398.2
GFI1B	ENST00000443690.3	n.281-1076A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33098 AN: 151904 Hom.: 3744 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.218

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33141 AN: 152024 Hom.: 3753 Cov.: 31 AF XY: 0.212 AC XY: 15732 AN XY: 74326

African (AFR) AF: 0.235 AC: 9719 AN: 41428

American (AMR) AF: 0.226 AC: 3452 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3468

East Asian (EAS) AF: 0.116 AC: 600 AN: 5164

South Asian (SAS) AF: 0.156 AC: 753 AN: 4828

European-Finnish (FIN) AF: 0.148 AC: 1570 AN: 10586

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15653 AN: 67962

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.225 Hom.: 489

Bravo AF: 0.225

Asia WGS AF: 0.166 AC: 581 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.99
DANN	Benign	0.51
PhyloP100		-0.21
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11243940; hg19: chr9-135821372;