9-132912369-A-T

Variant names:

• chr9-132912369-A-T
• NM_000368.5:c.826T>A

Variant summary

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

The NM_000368.5(TSC1):​c.826T>A​(p.Ser276Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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. S276P) 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: 2.57

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 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	c.826T>A	p.Ser276Thr	missense_variant	Exon 9 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.826T>A	p.Ser276Thr	missense_variant	Exon 9 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.826T>A	p.Ser276Thr	missense_variant	Exon 10 of 24	3		ENSP00000495533.2

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	0.088
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L;.;L;.;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.76	N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.13	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Benign	0.069	T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.0080	B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.
Vest4		0.53
MutPred		0.86		Loss of disorder (P = 0.055);.;Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);.;.;Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);Loss of disorder (P = 0.055);.;Loss of disorder (P = 0.055);.;
MVP		0.84
MPC		0.49
ClinPred		0.42	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.36

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: chr9-135787756;