rs118203742

Variant names:

• chr9-132896627-C-T
• rs118203742
• NM_000368.5:c.3103G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-132896627-C-T
• chr9-132896627-C-A
• chr9-132896627-C-G

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.3103G>A​(p.Gly1035Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,806 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. G1035D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20 O:2
• Conservation: PhyloP100: 0.846
• Publications: 20 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=0.005901724).
• BP6: Variant 9-132896627-C-T is Benign according to our data. Variant chr9-132896627-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41696.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00138 (210/152252) while in subpopulation NFE AF = 0.00215 (146/68016). AF 95% confidence interval is 0.00186. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 210 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.3103G>A	p.Gly1035Ser	missense	Exon 23 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.3103G>A	p.Gly1035Ser	missense	Exon 23 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.3103G>A	p.Gly1035Ser	missense	Exon 23 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.3103G>A	p.Gly1035Ser	missense	Exon 23 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.3103G>A	p.Gly1035Ser	missense	Exon 24 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.3103G>A	p.Gly1035Ser	missense	Exon 23 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00139 AC: 348 AN: 249584 AF XY: 0.00126

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00214 AC: 3126 AN: 1461554 Hom.: 6 Cov.: 31 AF XY: 0.00209 AC XY: 1520 AN XY: 727062

African (AFR) AF: 0.000299 AC: 10 AN: 33470

American (AMR) AF: 0.00150 AC: 67 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53364

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00255 AC: 2830 AN: 1111802

Other (OTH) AF: 0.00205 AC: 124 AN: 60380

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74462

African (AFR) AF: 0.000554 AC: 23 AN: 41538

American (AMR) AF: 0.00196 AC: 30 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00202 Hom.: 3

Bravo AF: 0.00156

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00289

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	1	4	not provided (5)
-	-	5	Tuberous sclerosis 1 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	Tuberous sclerosis syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.85
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.75	T
Polyphen		0.044	B
Vest4		0.11
MVP		0.75
MPC		0.50
ClinPred		0.0073	T
GERP RS		4.3
Varity_R		0.020
gMVP		0.15
Mutation Taster		=94/6	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: rs118203742; hg19: chr9-135772014; COSMIC: COSV53772381; COSMIC: COSV53772381;