chr9-132903723-A-C

Position:

• chr9-132903723-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000368.5(TSC1):​c.2136T>G​(p.His712Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2136T>G	p.His712Gln	missense_variant	17/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2136T>G	p.His712Gln	missense_variant	17/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2136T>G	p.His712Gln	missense_variant	18/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;D;.;.;D;.;D;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.5	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.86
MutPred		0.67		Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;.;Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;.;.;
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		-3.8
Varity_R		0.85
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135779110;