rs371225009

chr9-132912413-T-Achr9-132912413-T-Cchr9-132912413-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000368.5(TSC1):c.782A>T(p.Lys261Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K261R) 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: 6.27

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132912413-T-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, TSC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.782A>T	p.Lys261Ile	missense_variant	9/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.782A>T	p.Lys261Ile	missense_variant	9/23	1	NM_000368.5	P4

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.2	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Polyphen		1.0	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.
Vest4		0.81
MutPred		0.61		Loss of ubiquitination at K261 (P = 0.0081);.;Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);.;.;Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);Loss of ubiquitination at K261 (P = 0.0081);.;Loss of ubiquitination at K261 (P = 0.0081);.;
MVP		0.90
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr9-135787800;