NM_000368.5:c.549T>A

Variant names:

• chr9-132921933-A-T
• rs774398322
• NM_000368.5:c.549T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000368.5(TSC1):​c.549T>A​(p.Ser183Arg) 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 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. S183T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817
• Publications: 0 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_000368.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.549T>A	p.Ser183Arg	missense_variant	Exon 7 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.549T>A	p.Ser183Arg	missense_variant	Exon 7 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.549T>A	p.Ser183Arg	missense_variant	Exon 8 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;D;.;D;.;D;.;.;.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	.;D;D;D;.;.;.;D;D;.;D;.;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.82
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.016	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	D;.;D;.;D;.;D;.;.;.;.;D;D;D;.;.;.;D;.;.
Vest4		0.96
MutPred		0.84		Gain of methylation at S183 (P = 0.0075);.;Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);.;.;Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);Gain of methylation at S183 (P = 0.0075);.;Gain of methylation at S183 (P = 0.0075);.;Gain of methylation at S183 (P = 0.0075);
MVP		0.97
MPC		1.5
ClinPred		0.97	D
GERP RS		-0.024
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.80
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs774398322; hg19: chr9-135797320;