9-132911517-A-G

Variant names:

• chr9-132911517-A-G
• rs1073123
• NM_000368.5:c.965T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000368.5(TSC1):​c.965T>C​(p.Met322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,960 control chromosomes in the GnomAD database, including 15,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M322I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1825 hom., cov: 30)
  • Exomes 𝑓: 0.13 (13354 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24 O:4
• Conservation: PhyloP100: 1.44
• Publications: 72 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014866292).
• BP6: Variant 9-132911517-A-G is Benign according to our data. Variant chr9-132911517-A-G is described in ClinVar as Benign. ClinVar VariationId is 41700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

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.965T>C	p.Met322Thr	missense	Exon 10 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.965T>C	p.Met322Thr	missense	Exon 10 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.965T>C	p.Met322Thr	missense	Exon 10 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.965T>C	p.Met322Thr	missense	Exon 10 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.965T>C	p.Met322Thr	missense	Exon 11 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.965T>C	p.Met322Thr	missense	Exon 10 of 10	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22753 AN: 151420 Hom.: 1815 Cov.: 30

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0991

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.125 AC: 31461 AN: 251310 AF XY: 0.123

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0859

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0876

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.132 AC: 193548 AN: 1461420 Hom.: 13354 Cov.: 33 AF XY: 0.131 AC XY: 95315 AN XY: 727034

African (AFR) AF: 0.217 AC: 7267 AN: 33460

American (AMR) AF: 0.0891 AC: 3984 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3681 AN: 26130

East Asian (EAS) AF: 0.0711 AC: 2823 AN: 39698

South Asian (SAS) AF: 0.105 AC: 9050 AN: 86248

European-Finnish (FIN) AF: 0.104 AC: 5540 AN: 53410

Middle Eastern (MID) AF: 0.104 AC: 601 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 152529 AN: 1111606

Other (OTH) AF: 0.134 AC: 8073 AN: 60378

GnomAD4 genome AF: 0.150 AC: 22794 AN: 151540 Hom.: 1825 Cov.: 30 AF XY: 0.145 AC XY: 10723 AN XY: 74034

African (AFR) AF: 0.213 AC: 8770 AN: 41206

American (AMR) AF: 0.103 AC: 1566 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3466

East Asian (EAS) AF: 0.0849 AC: 436 AN: 5138

South Asian (SAS) AF: 0.103 AC: 497 AN: 4806

European-Finnish (FIN) AF: 0.104 AC: 1091 AN: 10520

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.140 AC: 9518 AN: 67908

Other (OTH) AF: 0.147 AC: 310 AN: 2108

Alfa AF: 0.144 Hom.: 7955

Bravo AF: 0.153

TwinsUK AF: 0.142 AC: 525

ALSPAC AF: 0.137 AC: 529

ESP6500AA AF: 0.219 AC: 967

ESP6500EA AF: 0.138 AC: 1185

ExAC AF: 0.129 AC: 15658

Asia WGS AF: 0.128 AC: 448 AN: 3478

EpiCase AF: 0.138

EpiControl AF: 0.141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	7	Tuberous sclerosis 1 (7)
-	-	4	not provided (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Malignant tumor of breast (1)
-	-	-	Malignant tumor of urinary bladder (1)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.39
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.033	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.26
Sift	Benign	0.77	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.58
ClinPred		0.00087	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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: rs1073123; hg19: chr9-135786904; COSMIC: COSV53763263; COSMIC: COSV53763263;