9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-132897613-G-GAAAAAAAAAA
• rs5901000
• NM_000368.5:c.2626-13_2626-4dupTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000368.5(TSC1):​c.2626-13_2626-4dupTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.517
• Publications: 0 publications found

Genes affected

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-13_2626-4dupTTTTTTTTTT		splice_region_variant, intron_variant	Intron 20 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-4_2626-3insTTTTTTTTTT		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-4_2626-3insTTTTTTTTTT		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.97e-7 AC: 1 AN: 1254020 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 623274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28216

American (AMR) AF: 0.00 AC: 0 AN: 27254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20218

East Asian (EAS) AF: 0.00 AC: 0 AN: 35462

South Asian (SAS) AF: 0.00 AC: 0 AN: 65666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 987722

Other (OTH) AF: 0.00 AC: 0 AN: 51766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;