9-132897613-GAAAAAAAAAAAA-GAAAAA

Variant names:

• chr9-132897613-GAAAAAAA-G
• rs5901000
• NM_000368.5:c.2626-10_2626-4delTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000368.5(TSC1):​c.2626-10_2626-4delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000399 in 1,254,016 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-10_2626-4delTTTTTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000399 AC: 5 AN: 1254016 Hom.: 0 AF XY: 0.00000481 AC XY: 3 AN XY: 623268

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

African (AFR) AF: 0.0000354 AC: 1 AN: 28216

American (AMR) AF: 0.00 AC: 0 AN: 27256

Ashkenazi Jewish (ASJ) AF: 0.0000495 AC: 1 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: 0.00000202 AC: 2 AN: 987718

Other (OTH) AF: 0.0000193 AC: 1 AN: 51764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00257888), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=74/26	polymorphism

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;