rs1554817166

chr9-132910686-C-Achr9-132910686-C-Gchr9-132910686-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_000368.5(TSC1):c.1148G>T(p.Gly383Val) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G383E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132910686-CC-CGAA is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1148G>T	p.Gly383Val	missense_variant	12/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1148G>T	p.Gly383Val	missense_variant	12/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.78
Sift	Benign	0.039	D;T;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;D;.;.;.;P;P;P;.;.
Vest4		0.69
MutPred		0.62		Loss of glycosylation at K384 (P = 0.1175);.;Loss of glycosylation at K384 (P = 0.1175);.;Loss of glycosylation at K384 (P = 0.1175);.;Loss of glycosylation at K384 (P = 0.1175);.;Loss of glycosylation at K384 (P = 0.1175);.;Loss of glycosylation at K384 (P = 0.1175);Loss of glycosylation at K384 (P = 0.1175);Loss of glycosylation at K384 (P = 0.1175);.;.;
MVP		0.64
MPC		1.3
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr9-135786073;