rs776386313

Variant names:

• chr9-132902715-A-C
• NM_000368.5:c.2281T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-132902715-A-C
• chr9-132902715-A-G
• chr9-132902715-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000368.5(TSC1):​c.2281T>G​(p.Tyr761Asp) 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. 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. Y761H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-132902715-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33848262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2281T>G	p.Tyr761Asp	missense_variant	Exon 18 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2281T>G	p.Tyr761Asp	missense_variant	Exon 18 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2281T>G	p.Tyr761Asp	missense_variant	Exon 19 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;T;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	.;T;T;T;T;.;.;.;T;T;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D;N;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.076	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.025	D;D;D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;D;.;D;.;.;.
Vest4		0.72
MutPred		0.30		Gain of ubiquitination at K756 (P = 0.0435);.;Gain of ubiquitination at K756 (P = 0.0435);.;.;Gain of ubiquitination at K756 (P = 0.0435);.;Gain of ubiquitination at K756 (P = 0.0435);.;.;.;
MVP		0.86
MPC		0.92
ClinPred		0.87	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.69

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: chr9-135778102;