rs116951280

chr9-132935081-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000368.5(TSC1):c.-129A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 399,072 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.014 (27 hom.)
• Consequence: TSC1 NM_000368.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.394

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

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 9-132935081-T-A is Benign according to our data. Variant chr9-132935081-T-A is described in ClinVar as [Benign]. Clinvar id is 64720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132935081-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0118 (1796/152328) while in subpopulation AMR AF= 0.0196 (300/15304). AF 95% confidence interval is 0.0178. There are 24 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1796 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.-129A>T		5_prime_UTR_variant	2/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.-129A>T		5_prime_UTR_variant	2/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1796 AN: 152210 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.0136 AC: 3352 AN: 246744 Hom.: 27 Cov.: 0 AF XY: 0.0139 AC XY: 1733 AN XY: 125064

Gnomad4 AFR exome AF: 0.00237

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000660

Gnomad4 FIN exome AF: 0.00527

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0118 AC: 1796 AN: 152328 Hom.: 24 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74494

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0107 Hom.: 1

Bravo AF: 0.0131

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2017	- -

Tuberous sclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Isolated focal cortical dysplasia type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Benign	0.86
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

LitVar

Other links and lift over

dbSNP: rs116951280; hg19: chr9-135810468; COSMIC: COSV53765199; COSMIC: COSV53765199;