chr9-132903664-T-A

Variant names:

• chr9-132903664-T-A
• NM_000368.5:c.2195A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000368.5(TSC1):​c.2195A>T​(p.His732Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H732Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38060597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2195A>T	p.His732Leu	missense_variant	Exon 17 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2195A>T	p.His732Leu	missense_variant	Exon 17 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2195A>T	p.His732Leu	missense_variant	Exon 18 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H732L variant (also known as c.2195A>T), located in coding exon 15 of the TSC1 gene, results from an A to T substitution at nucleotide position 2195. The histidine at codon 732 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.82	D;.;D;.;.;D;.;D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.6	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D;D;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.12	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.043	D;D;D;.;.;.;.;.;.;.;.
Polyphen		0.98	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.60
MutPred		0.20		Loss of catalytic residue at N733 (P = 0.08);.;Loss of catalytic residue at N733 (P = 0.08);.;.;Loss of catalytic residue at N733 (P = 0.08);.;Loss of catalytic residue at N733 (P = 0.08);.;.;.;
MVP		0.49
MPC		0.63
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.49
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr9-135779051;