rs143502728

chr9-132910617-T-Achr9-132910617-T-Cchr9-132910617-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000368.5(TSC1):c.1217A>T(p.Tyr406Phe) 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. 15/20 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. Y406C) 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: 0.230

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_benign. 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=0.043932676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1217A>T	p.Tyr406Phe	missense_variant	12/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1217A>T	p.Tyr406Phe	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	0.071
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	4.5
Dann	Benign	0.62
DEOGEN2	Benign	0.38	T;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.044	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;.;L;.;L;.;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.41	N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.71	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;.;B;.;B;.;B;.;.;.;B;B;B;.
Vest4		0.20
MutPred		0.38		Loss of phosphorylation at Y406 (P = 0.0017);.;Loss of phosphorylation at Y406 (P = 0.0017);.;Loss of phosphorylation at Y406 (P = 0.0017);.;Loss of phosphorylation at Y406 (P = 0.0017);.;Loss of phosphorylation at Y406 (P = 0.0017);.;Loss of phosphorylation at Y406 (P = 0.0017);Loss of phosphorylation at Y406 (P = 0.0017);Loss of phosphorylation at Y406 (P = 0.0017);.;
MVP		0.33
MPC		0.46
ClinPred		0.038	T
GERP RS		-1.1
Varity_R		0.029
gMVP		0.24

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: chr9-135786004;