rs1033463168

chr9-132897269-C-Achr9-132897269-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000368.5(TSC1):c.2890G>T(p.Asp964Tyr) 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. 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. D964N) 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: 2.86

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TSC1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2890G>T	p.Asp964Tyr	missense_variant	22/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2890G>T	p.Asp964Tyr	missense_variant	22/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;D;.;.;D;.;D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.2	M;.;M;.;.;M;.;M;.;.;.
MutationTaster	Benign	0.59	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.045	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.98	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.72
MutPred		0.28		Loss of disorder (P = 0.0366);.;Loss of disorder (P = 0.0366);.;.;Loss of disorder (P = 0.0366);.;Loss of disorder (P = 0.0366);.;.;.;
MVP		0.62
MPC		1.4
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.60
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: -14

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: chr9-135772656; COSMIC: COSV105149008; COSMIC: COSV105149008;