Genetic Variant NM_000368.5:c.973C>A (chr9-132911509-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000368.5(TSC1):c.973C>A(p.Gln325Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSC1
NM_000368.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Variant links:

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]

TSC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5 link	c.973C>A	p.Gln325Lys	missense_variant	Exon 10 of 23	ENST00000298552.9	NP_000359.1	Q92574-1Q86WV8X5D9D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9 link	c.973C>A	p.Gln325Lys	missense_variant	Exon 10 of 23	1	NM_000368.5	ENSP00000298552.3		Q92574-1
TSC1	ENST00000490179.4 link	c.973C>A	p.Gln325Lys	missense_variant	Exon 11 of 24	3		ENSP00000495533.2		A0A2R8Y6S8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.3

M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.53

N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N

REVEL

Uncertain

0.56

Sift

Benign

0.75

T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T

Sift4G

Benign

0.17

T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T

Polyphen

0.81

P;.;P;.;P;.;P;.;.;.;.;D;D;D;.;.;.;P

Vest4

0.55

MutPred

0.49

Gain of ubiquitination at Q325 (P = 0.0094);.;Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);.;.;Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);Gain of ubiquitination at Q325 (P = 0.0094);.;Gain of ubiquitination at Q325 (P = 0.0094);

MVP

0.86

MPC

0.82

ClinPred

0.62

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.38

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over