9-132905878-G-T

Variant names:

• chr9-132905878-G-T
• NM_000368.5:c.1700C>A

Variant summary

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

The NM_000368.5(TSC1):​c.1700C>A​(p.Ala567Glu) 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. A567V) has been classified as 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: 4.18

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=0.4116575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1700C>A	p.Ala567Glu	missense_variant	Exon 15 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1700C>A	p.Ala567Glu	missense_variant	Exon 15 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1700C>A	p.Ala567Glu	missense_variant	Exon 16 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

Feb 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A567E variant (also known as c.1700C>A), located in coding exon 13 of the TSC1 gene, results from a C to A substitution at nucleotide position 1700. The alanine at codon 567 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;.;.;.;D;D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;M;.;M;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.034	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.20	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.87	P;.;P;.;.;P;.;P;.;.;.
Vest4		0.60
MutPred		0.58		Loss of catalytic residue at A567 (P = 0.0591);.;Loss of catalytic residue at A567 (P = 0.0591);.;.;Loss of catalytic residue at A567 (P = 0.0591);.;Loss of catalytic residue at A567 (P = 0.0591);.;Loss of catalytic residue at A567 (P = 0.0591);.;
MVP		0.79
MPC		1.3
ClinPred		0.57	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.37

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: chr9-135781265;