9-132911457-G-T

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.1025C>A(p.Pro342Gln) 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. 14/21 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. P342S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91

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 chr9-132911456-TG-TTTGT is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15625253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1025C>A	p.Pro342Gln	missense_variant	10/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1025C>A	p.Pro342Gln	missense_variant	10/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457448 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	18
Dann	Benign	0.76
DEOGEN2	Benign	0.41	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.14	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.68	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.65	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0020	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B
Vest4		0.21
MutPred		0.57		Loss of catalytic residue at P341 (P = 0.0135);.;Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);.;.;Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);Loss of catalytic residue at P341 (P = 0.0135);.;Loss of catalytic residue at P341 (P = 0.0135);
MVP		0.89
MPC		0.47
ClinPred		0.15	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.15

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: chr9-135786844;