9-132897610-C-T

Variant names:

• chr9-132897610-C-T
• rs747602915
• NM_000368.5:c.2626G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000368.5(TSC1):​c.2626G>A​(p.Glu876Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000854 in 1,170,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E876E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.49
• Publications: 4 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2626G>A	p.Glu876Lys	missense splice_region	Exon 21 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626G>A	p.Glu876Lys	missense splice_region	Exon 21 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626G>A	p.Glu876Lys	missense splice_region	Exon 21 of 23	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.2626G>A	p.Glu876Lys	missense splice_region	Exon 21 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626G>A	p.Glu876Lys	missense splice_region	Exon 22 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626G>A	p.Glu876Lys	missense splice_region	Exon 21 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 8.54e-7 AC: 1 AN: 1170912 Hom.: 0 Cov.: 42 AF XY: 0.00000171 AC XY: 1 AN XY: 585900

⚠️ 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: 27928

American (AMR) AF: 0.00 AC: 0 AN: 29696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20118

East Asian (EAS) AF: 0.00 AC: 0 AN: 33416

South Asian (SAS) AF: 0.00 AC: 0 AN: 63692

European-Finnish (FIN) AF: 0.0000272 AC: 1 AN: 36792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4806

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 906024

Other (OTH) AF: 0.00 AC: 0 AN: 48440

⚠️ 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.: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)
-	1	-	not provided (1)
-	1	-	Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.58
Sift	Benign	0.083	T
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.24		Gain of MoRF binding (P = 0.0022)
MVP		0.84
MPC		1.5
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.61
gMVP		0.50
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
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: rs747602915; hg19: chr9-135772997;