rs739442

Variant names:

• chr9-132894747-G-A
• rs739442
• NM_000368.5:c.*1488C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132894747-G-A
• chr9-132894747-G-T

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.*1488C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 217,942 control chromosomes in the GnomAD database, including 28,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18187 hom., cov: 29)
  • Exomes 𝑓: 0.52 (9954 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.581
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-132894747-G-A is Benign according to our data. Variant chr9-132894747-G-A is described in ClinVar as Benign. ClinVar VariationId is 365477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.*1488C>T		3_prime_UTR	Exon 23 of 23	NP_000359.1
	TSC1	NR_176214.1		n.5033C>T		non_coding_transcript_exon	Exon 22 of 22
	TSC1	NR_176215.1		n.5195C>T		non_coding_transcript_exon	Exon 23 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.*1488C>T		3_prime_UTR	Exon 23 of 23	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.*1488C>T		3_prime_UTR	Exon 24 of 24	ENSP00000495533.2
	TSC1	ENST00000642261.2		n.*2839C>T		non_coding_transcript_exon	Exon 22 of 22	ENSP00000494743.2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67595 AN: 150714 Hom.: 18192 Cov.: 29

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.524 AC: 35222 AN: 67156 Hom.: 9954 Cov.: 0 AF XY: 0.531 AC XY: 16497 AN XY: 31080

African (AFR) AF: 0.114 AC: 384 AN: 3368

American (AMR) AF: 0.433 AC: 879 AN: 2028

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2570 AN: 4238

East Asian (EAS) AF: 0.535 AC: 5313 AN: 9926

South Asian (SAS) AF: 0.584 AC: 320 AN: 548

European-Finnish (FIN) AF: 0.521 AC: 25 AN: 48

Middle Eastern (MID) AF: 0.459 AC: 192 AN: 418

European-Non Finnish (NFE) AF: 0.555 AC: 22776 AN: 41040

Other (OTH) AF: 0.499 AC: 2763 AN: 5542

GnomAD4 genome AF: 0.448 AC: 67590 AN: 150786 Hom.: 18187 Cov.: 29 AF XY: 0.455 AC XY: 33455 AN XY: 73518

African (AFR) AF: 0.128 AC: 5256 AN: 40908

American (AMR) AF: 0.490 AC: 7432 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2105 AN: 3466

East Asian (EAS) AF: 0.575 AC: 2952 AN: 5130

South Asian (SAS) AF: 0.641 AC: 3081 AN: 4804

European-Finnish (FIN) AF: 0.615 AC: 6300 AN: 10240

Middle Eastern (MID) AF: 0.458 AC: 132 AN: 288

European-Non Finnish (NFE) AF: 0.573 AC: 38863 AN: 67794

Other (OTH) AF: 0.466 AC: 973 AN: 2090

Alfa AF: 0.519 Hom.: 26200

Bravo AF: 0.418

Asia WGS AF: 0.581 AC: 2015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Isolated focal cortical dysplasia type II Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Tuberous sclerosis 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.30
DANN	Benign	0.67
PhyloP100		-0.58
Mutation Taster		=100/0	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: rs739442; hg19: chr9-135770134; COSMIC: COSV53765006; COSMIC: COSV53765006;