rs1554817122

Positions:

• chr9-132910611-T-A
• chr9-132910611-T-C
• chr9-132910611-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000368.5(TSC1):​c.1223A>T​(p.His408Leu) 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. 13/21 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. H408P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17

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
• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.18237263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1223A>T	p.His408Leu	missense_variant	12/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1223A>T	p.His408Leu	missense_variant	12/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	0.0097
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;.;M;.;M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.38	N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.51	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.44	T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.34	B;.;B;.;B;.;B;.;.;.;P;P;P;.
Vest4		0.69
MutPred		0.47		Gain of stability (P = 0.0538);.;Gain of stability (P = 0.0538);.;Gain of stability (P = 0.0538);.;Gain of stability (P = 0.0538);.;Gain of stability (P = 0.0538);.;Gain of stability (P = 0.0538);Gain of stability (P = 0.0538);Gain of stability (P = 0.0538);.;
MVP		0.78
MPC		0.75
ClinPred		0.18	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr9-135785998;