rs10901220

chr9-132906176-G-A

Variant summary

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

The NM_000368.5(TSC1):c.1439-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,596,800 control chromosomes in the GnomAD database, including 16,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1982 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14948 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.466

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=-0.86).
• BP6: Variant 9-132906176-G-A is Benign according to our data. Variant chr9-132906176-G-A is described in ClinVar as [Benign]. Clinvar id is 48784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906176-G-A 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/exons	MANE	UniProt
TSC1	NM_000368.5	c.1439-37C>T		intron_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1439-37C>T		intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23788 AN: 152046 Hom.: 1972 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0845

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.134 AC: 28969 AN: 216852 Hom.: 1953 AF XY: 0.132 AC XY: 15670 AN XY: 118614

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0897

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0897

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.142 AC: 204534 AN: 1444636 Hom.: 14948 Cov.: 30 AF XY: 0.140 AC XY: 100430 AN XY: 717480

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0918

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.157 AC: 23828 AN: 152164 Hom.: 1982 Cov.: 32 AF XY: 0.151 AC XY: 11229 AN XY: 74392

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.153

Alfa AF: 0.151 Hom.: 958

Bravo AF: 0.159

Asia WGS AF: 0.130 AC: 453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2018

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Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.9
Dann	Benign	0.44
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: rs10901220; hg19: chr9-135781563; COSMIC: COSV53775582; COSMIC: COSV53775582;