rs576476807

chr9-132897553-C-Achr9-132897553-C-Gchr9-132897553-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000368.5(TSC1):c.2683G>T(p.Val895Phe) 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. 13/20 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. V895I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1407232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2683G>T	p.Val895Phe	missense_variant	21/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2683G>T	p.Val895Phe	missense_variant	21/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0038	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.67	N;N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.21	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.60	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.26	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.58
MutPred		0.22		Loss of MoRF binding (P = 0.1339);.;Loss of MoRF binding (P = 0.1339);.;.;Loss of MoRF binding (P = 0.1339);.;Loss of MoRF binding (P = 0.1339);.;.;.;
MVP		0.30
MPC		0.68
ClinPred		0.25	T
GERP RS		2.3
Varity_R		0.27
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr9-135772940;