9-132897612-T-TCA

Variant names:

• chr9-132897612-T-TCA
• rs760737807
• NM_000368.5:c.2626-3_2626-2insTG

Variant summary

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

The NM_000368.5(TSC1):​c.2626-3_2626-2insTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 871,500 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.387
• 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.2626-3_2626-2insTG		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.2626-3_2626-2insTG		splice_region_variant, intron_variant	Intron 20 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-3_2626-2insTG		splice_region_variant, intron_variant	Intron 21 of 23	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome AF: 0.0000103 AC: 9 AN: 871500 Hom.: 0 Cov.: 27 AF XY: 0.00000911 AC XY: 4 AN XY: 438846

⚠️ 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: 23542

American (AMR) AF: 0.0000440 AC: 1 AN: 22740

Ashkenazi Jewish (ASJ) AF: 0.0000650 AC: 1 AN: 15378

East Asian (EAS) AF: 0.00 AC: 0 AN: 29854

South Asian (SAS) AF: 0.00 AC: 0 AN: 41896

European-Finnish (FIN) AF: 0.0000349 AC: 1 AN: 28664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3220

European-Non Finnish (NFE) AF: 0.00000897 AC: 6 AN: 668766

Other (OTH) AF: 0.00 AC: 0 AN: 37440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

Splicing

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

Other links and lift over

dbSNP: rs760737807; hg19: chr9-135772999;