rs1554815018

chr9-132902714-T-Achr9-132902714-T-Cchr9-132902714-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000368.5(TSC1):c.2282A>T(p.Tyr761Phe) variant causes a missense change. 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. Y761H) 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: 3.85

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132902715-A-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.25024343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2282A>T	p.Tyr761Phe	missense_variant	18/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2282A>T	p.Tyr761Phe	missense_variant	18/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.26	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.081	T;T;T;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.55
MutPred		0.16		Loss of phosphorylation at Y761 (P = 0.0506);.;Loss of phosphorylation at Y761 (P = 0.0506);.;.;Loss of phosphorylation at Y761 (P = 0.0506);.;Loss of phosphorylation at Y761 (P = 0.0506);.;.;.;
MVP		0.76
MPC		0.46
ClinPred		0.74	D
GERP RS		5.7
Varity_R		0.30
gMVP		0.14

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: chr9-135778101;