rs7872606

Positions:

• chr9-132906890-G-C

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.1334-55C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 1,371,562 control chromosomes in the GnomAD database, including 6,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (651 hom., cov: 32)
  • Exomes 𝑓: 0.095 (5472 hom.)
• Consequence: TSC1 ENST00000298552.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.00900

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=-0.9).
• BP6: Variant 9-132906890-G-C is Benign according to our data. Variant chr9-132906890-G-C is described in ClinVar as [Benign]. Clinvar id is 48767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906890-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1334-55C>G		intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1334-55C>G		intron_variant		1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes AF: 0.0929 AC: 14133 AN: 152050 Hom.: 650 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.0837

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0961

Gnomad OTH AF: 0.0886

GnomAD4 exome AF: 0.0954 AC: 116339 AN: 1219394 Hom.: 5472 AF XY: 0.0942 AC XY: 58235 AN XY: 618250

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0557

Gnomad4 ASJ exome AF: 0.0838

Gnomad4 EAS exome AF: 0.0705

Gnomad4 SAS exome AF: 0.0734

Gnomad4 FIN exome AF: 0.0903

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.0944

GnomAD4 genome AF: 0.0929 AC: 14144 AN: 152168 Hom.: 651 Cov.: 32 AF XY: 0.0901 AC XY: 6703 AN XY: 74392

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0581

Gnomad4 ASJ AF: 0.0772

Gnomad4 EAS AF: 0.0838

Gnomad4 SAS AF: 0.0777

Gnomad4 FIN AF: 0.0907

Gnomad4 NFE AF: 0.0961

Gnomad4 OTH AF: 0.0896

Alfa AF: 0.102 Hom.: 104

Bravo AF: 0.0910

Asia WGS AF: 0.0880 AC: 308 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

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	-0.90
CADD	Benign	2.2
DANN	Benign	0.37

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: rs7872606; hg19: chr9-135782277; COSMIC: COSV53764084; COSMIC: COSV53764084;