rs118203481

Variant names:

• chr9-132911481-G-A
• rs118203481
• NM_000368.5:c.1001C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132911481-G-A
• chr9-132911481-G-C
• chr9-132911481-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406629.1(TSC1):​c.-93C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,613,700 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: TSC1 NM_001406629.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19 O:2
• Conservation: PhyloP100: 2.44
• Publications: 12 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=0.015584558).
• BP6: Variant 9-132911481-G-A is Benign according to our data. Variant chr9-132911481-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000253 (370/1461610) while in subpopulation SAS AF = 0.00247 (213/86254). AF 95% confidence interval is 0.0022. There are 2 homozygotes in GnomAdExome4. There are 240 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406629.1. 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.1001C>T	p.Ser334Leu	missense	Exon 10 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406629.1		c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 22	NP_001393558.1
	TSC1	NM_001406630.1		c.-93C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 of 23	NP_001393559.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.1001C>T	p.Ser334Leu	missense	Exon 10 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.1001C>T	p.Ser334Leu	missense	Exon 11 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000403810.6	TSL:1	c.1001C>T	p.Ser334Leu	missense	Exon 10 of 10	ENSP00000386093.1	Q86WV8

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151972 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000426 AC: 107 AN: 251326 AF XY: 0.000560

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1461610 Hom.: 2 Cov.: 32 AF XY: 0.000330 AC XY: 240 AN XY: 727148

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00247 AC: 213 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111752

Other (OTH) AF: 0.000232 AC: 14 AN: 60384

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74368

African (AFR) AF: 0.0000964 AC: 4 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	4	Tuberous sclerosis 1 (4)
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Isolated focal cortical dysplasia type II (1)
-	-	1	TSC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.43
Sift	Benign	0.096	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.19
MVP		0.89
MPC		0.44
ClinPred		0.021	T
GERP RS		4.7
Varity_R		0.071
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs118203481; hg19: chr9-135786868;