rs118203512

chr9-132907303-G-Achr9-132907303-G-Cchr9-132907303-G-T

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.1331C>T(p.Ser444Leu) variant causes a missense, splice region 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S444T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense, splice_region
• Scores: Splicing: ADA: 0.1142
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508

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=0.048084974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1331C>T	p.Ser444Leu	missense_variant, splice_region_variant	13/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1331C>T	p.Ser444Leu	missense_variant, splice_region_variant	13/23	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	0.054
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
Dann	Benign	0.92
DEOGEN2	Uncertain	0.45	T;.;T;.;.;T;.;T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0056	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.048	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.7	N;.;N;.;.;N;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.75	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.10	T;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.32	T;T;T;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;.;B;.;B;.;.;.;.
Vest4		0.084
MutPred		0.46		Gain of catalytic residue at S444 (P = 0.001);.;Gain of catalytic residue at S444 (P = 0.001);.;.;Gain of catalytic residue at S444 (P = 0.001);.;Gain of catalytic residue at S444 (P = 0.001);.;Gain of catalytic residue at S444 (P = 0.001);.;.;
MVP		0.25
MPC		0.44
ClinPred		0.13	T
GERP RS		0.059
Varity_R		0.053
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.010		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: chr9-135782690;