chr9-132892556-C-T

Position:

• chr9-132892556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000298552.9(TSC1):​c.*3679G>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 0.697 in 233,098 control chromosomes in the GnomAD database, including 56,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36245 hom., cov: 32)
  • Exomes 𝑓: 0.71 (20694 hom.)
• Consequence: TSC1 ENST00000298552.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-132892556-C-T is Benign according to our data. Variant chr9-132892556-C-T is described in ClinVar as [Benign]. Clinvar id is 365414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132892556-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.*3679G>A		3_prime_UTR_variant	23/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.*3679G>A		3_prime_UTR_variant	23/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104476 AN: 151944 Hom.: 36217 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.671

GnomAD4 exome AF: 0.714 AC: 57832 AN: 81036 Hom.: 20694 Cov.: 0 AF XY: 0.716 AC XY: 26708 AN XY: 37282

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.634

Gnomad4 ASJ exome AF: 0.751

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.815

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.703

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.688 AC: 104556 AN: 152062 Hom.: 36245 Cov.: 32 AF XY: 0.694 AC XY: 51582 AN XY: 74348

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.741

Gnomad4 EAS AF: 0.810

Gnomad4 SAS AF: 0.820

Gnomad4 FIN AF: 0.795

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.675

Alfa AF: 0.696 Hom.: 49092

Bravo AF: 0.669

Asia WGS AF: 0.817 AC: 2840 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Tuberous sclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1050700; hg19: chr9-135767943;