9-132925638-C-G

Variant names:

• chr9-132925638-C-G
• NM_000368.5:c.312G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000368.5(TSC1):​c.312G>C​(p.Lys104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.312G>C	p.Lys104Asn	missense_variant	Exon 5 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.312G>C	p.Lys104Asn	missense_variant	Exon 5 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.312G>C	p.Lys104Asn	missense_variant	Exon 6 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.;T;.;T;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;D;D;.;.;.;D;D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.3	M;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.82	N;N;.;.;.;.;.;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.016	D;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		0.98	D;D;.;D;.;D;.;.;D;D;D;.;.;D;.;.
Vest4		0.73
MutPred		0.47		Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);Loss of methylation at K104 (P = 0.0273);
MVP		0.88
MPC		1.5
ClinPred		0.86	D
GERP RS		2.5
Varity_R		0.23
gMVP		0.48

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: chr9-135801025;