9-132891798-C-T

Variant names:

• chr9-132891798-C-T
• rs11553763
• NM_000368.5:c.*4437G>A

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.*4437G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 233,568 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1450 hom., cov: 33)
  • Exomes 𝑓: 0.084 (315 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.820

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-132891798-C-T is Benign according to our data. Variant chr9-132891798-C-T is described in ClinVar as [Benign]. Clinvar id is 365392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132891798-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.*4437G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.*4437G>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.*4437G>A		3_prime_UTR_variant	Exon 24 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17495 AN: 152100 Hom.: 1443 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0714

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.0836 AC: 6799 AN: 81350 Hom.: 315 Cov.: 0 AF XY: 0.0816 AC XY: 3055 AN XY: 37450

African (AFR) AF: 0.218 AC: 850 AN: 3892

American (AMR) AF: 0.154 AC: 384 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 277 AN: 5120

East Asian (EAS) AF: 0.0652 AC: 743 AN: 11398

South Asian (SAS) AF: 0.0456 AC: 32 AN: 702

European-Finnish (FIN) AF: 0.0519 AC: 25 AN: 482

Middle Eastern (MID) AF: 0.0711 AC: 35 AN: 492

European-Non Finnish (NFE) AF: 0.0757 AC: 3784 AN: 50000

Other (OTH) AF: 0.0988 AC: 669 AN: 6768

GnomAD4 genome AF: 0.115 AC: 17538 AN: 152218 Hom.: 1450 Cov.: 33 AF XY: 0.113 AC XY: 8421 AN XY: 74422

African (AFR) AF: 0.215 AC: 8918 AN: 41488

American (AMR) AF: 0.151 AC: 2305 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.0555 AC: 288 AN: 5190

South Asian (SAS) AF: 0.0510 AC: 246 AN: 4826

European-Finnish (FIN) AF: 0.0366 AC: 388 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0714 AC: 4855 AN: 68030

Other (OTH) AF: 0.116 AC: 246 AN: 2112

Alfa AF: 0.0948 Hom.: 1091

Bravo AF: 0.130

Asia WGS AF: 0.0690 AC: 241 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 12, 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 12, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		0.82
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

Publications

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Other links and lift over

dbSNP: rs11553763; hg19: chr9-135767185;