chr9-132906028-C-G

Variant names:

• chr9-132906028-C-G
• rs371908551
• NM_000368.5:c.1550G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000368.5(TSC1):​c.1550G>C​(p.Arg517Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R517Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 15 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1550G>C	p.Arg517Pro	missense_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1550G>C	p.Arg517Pro	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1550G>C	p.Arg517Pro	missense_variant	Exon 16 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;D;.;.;D;.;D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.3	M;.;M;.;.;M;.;M;.;.;.
PhyloP100		2.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.014	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.34	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.96	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.47
MutPred		0.54		Gain of glycosylation at R517 (P = 0.0411);.;Gain of glycosylation at R517 (P = 0.0411);.;.;Gain of glycosylation at R517 (P = 0.0411);.;Gain of glycosylation at R517 (P = 0.0411);.;Gain of glycosylation at R517 (P = 0.0411);.;
MVP		0.74
MPC		1.7
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.33
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

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Other links and lift over

dbSNP: rs371908551; hg19: chr9-135781415;