chr9-132921376-G-C

Position:

• chr9-132921376-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000368.5(TSC1):​c.724C>G​(p.Leu242Val) variant causes a missense change involving the alteration of a 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. L242P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TSC1. . Gene score misZ 2.3217 (greater than the threshold 3.09). Trascript score misZ 3.6986 (greater than threshold 3.09). GenCC has associacion of gene with lung lymphangioleiomyomatosis, tuberous sclerosis 1, tuberous sclerosis, tuberous sclerosis complex, lymphangioleiomyomatosis.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.724C>G	p.Leu242Val	missense_variant	8/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.724C>G	p.Leu242Val	missense_variant	8/23	1	NM_000368.5	P4

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	0.24
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.36	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.41	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Sift4G	Benign	0.17	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.38	B;.;B;.;B;.;B;.;.;.;.;D;D;D;.;.;.;P;.
Vest4		0.76
MutPred		0.64		Loss of ubiquitination at K238 (P = 0.0692);.;Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);.;.;Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);Loss of ubiquitination at K238 (P = 0.0692);.;Loss of ubiquitination at K238 (P = 0.0692);.;
MVP		0.66
MPC		1.2
ClinPred		0.86	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135796763;