NM_000368.5:c.2194C>T

Variant names:

• chr9-132903665-G-A
• rs118203657
• NM_000368.5:c.2194C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000368.5(TSC1):​c.2194C>T​(p.His732Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,612,416 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H732R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (24 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:28 O:2
• Conservation: PhyloP100: 8.07
• Publications: 40 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00885722).
• BP6: Variant 9-132903665-G-A is Benign according to our data. Variant chr9-132903665-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5103.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00326 (497/152322) while in subpopulation NFE AF = 0.00463 (315/68032). AF 95% confidence interval is 0.00421. There are 4 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 497 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2194C>T	p.His732Tyr	missense	Exon 17 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2194C>T	p.His732Tyr	missense	Exon 17 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2194C>T	p.His732Tyr	missense	Exon 17 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2194C>T	p.His732Tyr	missense	Exon 17 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2194C>T	p.His732Tyr	missense	Exon 18 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2194C>T	p.His732Tyr	missense	Exon 17 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152204 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00364 AC: 914 AN: 251112 AF XY: 0.00357

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00364 AC: 5309 AN: 1460094 Hom.: 24 Cov.: 32 AF XY: 0.00348 AC XY: 2527 AN XY: 726338

African (AFR) AF: 0.000449 AC: 15 AN: 33424

American (AMR) AF: 0.00125 AC: 56 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86176

European-Finnish (FIN) AF: 0.0140 AC: 750 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4376

European-Non Finnish (NFE) AF: 0.00387 AC: 4304 AN: 1111920

Other (OTH) AF: 0.00302 AC: 182 AN: 60232

GnomAD4 genome AF: 0.00326 AC: 497 AN: 152322 Hom.: 4 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74480

African (AFR) AF: 0.000601 AC: 25 AN: 41572

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00342 Hom.: 3

Bravo AF: 0.00213

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00386 AC: 469

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	8	not provided (8)
-	-	7	Tuberous sclerosis 1 (7)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	Isolated focal cortical dysplasia type II (2)
-	1	-	Focal cortical dysplasia of Taylor type 2B (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.44
MVP		0.56
MPC		0.58
ClinPred		0.045	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.64
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs118203657; hg19: chr9-135779052; COSMIC: COSV104404438; COSMIC: COSV104404438;