9-132906890-G-C

Variant names:

• chr9-132906890-G-C
• rs7872606
• NM_000368.5:c.1334-55C>G

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.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 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.00900
• Publications: 5 publications found

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]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 48767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1334-55C>G		intron_variant	Intron 13 of 22	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1334-55C>G		intron_variant	Intron 13 of 22	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1334-55C>G		intron_variant	Intron 14 of 23	3		ENSP00000495533.2

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

African (AFR) AF: 0.113 AC: 3235 AN: 28740

American (AMR) AF: 0.0557 AC: 2447 AN: 43908

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 2061 AN: 24594

East Asian (EAS) AF: 0.0705 AC: 2714 AN: 38518

South Asian (SAS) AF: 0.0734 AC: 5922 AN: 80686

European-Finnish (FIN) AF: 0.0903 AC: 4612 AN: 51078

Middle Eastern (MID) AF: 0.0553 AC: 291 AN: 5262

European-Non Finnish (NFE) AF: 0.101 AC: 90132 AN: 894424

Other (OTH) AF: 0.0944 AC: 4925 AN: 52184

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

African (AFR) AF: 0.107 AC: 4437 AN: 41510

American (AMR) AF: 0.0581 AC: 888 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3470

East Asian (EAS) AF: 0.0838 AC: 434 AN: 5176

South Asian (SAS) AF: 0.0777 AC: 374 AN: 4814

European-Finnish (FIN) AF: 0.0907 AC: 960 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0961 AC: 6535 AN: 68010

Other (OTH) AF: 0.0896 AC: 189 AN: 2110

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

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.37
PhyloP100		-0.0090
PromoterAI		0.0014	Neutral
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

Other links and lift over

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