rs12380834

Variant names:

• chr9-132946495-A-G
• rs12380834
• ENST00000339463.7:c.-701+826A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132946495-A-G
• chr9-132946495-A-T

Variant summary

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

The ENST00000339463.7(GFI1B):​c.-701+826A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,024 control chromosomes in the GnomAD database, including 3,639 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 (3639 hom., cov: 31)
  • Exomes 𝑓: 0.038 (0 hom.)
• Consequence: GFI1B ENST00000339463.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.190
• Publications: 1 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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFI1B	NM_004188.8	c.-701+826A>G		intron_variant	Intron 1 of 10		NP_004179.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFI1B	ENST00000339463.7	c.-701+826A>G		intron_variant	Intron 1 of 10	1		ENSP00000344782.3
TSC1	ENST00000643362.2	c.-144+264T>C		intron_variant	Intron 1 of 19			ENSP00000496398.2
GFI1B	ENST00000443690.3	n.281-566A>G		intron_variant	Intron 2 of 3	5
GFI1B	ENST00000631293.1	n.67-102A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32660 AN: 151880 Hom.: 3628 Cov.: 31

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.0385 AC: 1 AN: 26 Hom.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.215 AC: 32716 AN: 151998 Hom.: 3639 Cov.: 31 AF XY: 0.209 AC XY: 15535 AN XY: 74302

African (AFR) AF: 0.234 AC: 9701 AN: 41412

American (AMR) AF: 0.221 AC: 3379 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3464

East Asian (EAS) AF: 0.115 AC: 598 AN: 5180

South Asian (SAS) AF: 0.156 AC: 750 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1570 AN: 10582

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

European-Non Finnish (NFE) AF: 0.226 AC: 15339 AN: 67952

Other (OTH) AF: 0.215 AC: 455 AN: 2112

Alfa AF: 0.214 Hom.: 524

Bravo AF: 0.222

Asia WGS AF: 0.168 AC: 587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.1
DANN	Benign	0.66
PhyloP100		0.19
PromoterAI		-0.0091	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: rs12380834; hg19: chr9-135821882;