9-132925700-C-G

Variant names:

• chr9-132925700-C-G
• NM_000368.5:c.250G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000368.5(TSC1):​c.250G>C​(p.Ala84Pro) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16725242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.250G>C	p.Ala84Pro	missense_variant	Exon 5 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.250G>C	p.Ala84Pro	missense_variant	Exon 5 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.250G>C	p.Ala84Pro	missense_variant	Exon 6 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Uncertain	0.45	T;T;.;T;.;T;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.74	.;T;T;.;.;.;T;T;.;.;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.7	L;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.22	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.32	T;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.35	T;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Polyphen		0.0020	B;B;.;B;.;B;.;.;D;D;D;.;.;D;.;.
Vest4		0.43
MutPred		0.54		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.44
MPC		1.5
ClinPred		0.40	T
GERP RS		-0.86
Varity_R		0.062
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr9-135801087;