9-132911457-G-C

Variant names:

• chr9-132911457-G-C
• NM_000368.5:c.1025C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000368.5(TSC1):​c.1025C>G​(p.Pro342Arg) 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. 12/21 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. P342HK) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132911456-TG-TTTGT is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21307236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1025C>G	p.Pro342Arg	missense_variant	Exon 10 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1025C>G	p.Pro342Arg	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1025C>G	p.Pro342Arg	missense_variant	Exon 11 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Uncertain	0.49	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.9	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.98	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.53
Sift	Benign	0.52	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.56	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.12	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B
Vest4		0.43
MutPred		0.59		Loss of catalytic residue at P341 (P = 0.0096);.;Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);.;.;Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);Loss of catalytic residue at P341 (P = 0.0096);.;Loss of catalytic residue at P341 (P = 0.0096);
MVP		0.95
MPC		0.56
ClinPred		0.12	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr9-135786844;