rs118203507

chr9-132910483-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000368.5(TSC1):c.1263+88A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,606,576 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (12 hom.)
• Consequence: TSC1 NM_000368.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:2 O:3
• Conservation: PhyloP100: -1.25

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005337715).
• BP6: Variant 9-132910483-T-C is Benign according to our data. Variant chr9-132910483-T-C is described in ClinVar as [Benign]. Clinvar id is 41689.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-132910483-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (366/152356) while in subpopulation NFE AF= 0.00438 (298/68046). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1263+88A>G		intron_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1263+88A>G		intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00236 AC: 588 AN: 248920 Hom.: 2 AF XY: 0.00242 AC XY: 326 AN XY: 134592

Gnomad AFR exome AF: 0.000688

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00369 AC: 5368 AN: 1454220 Hom.: 12 Cov.: 31 AF XY: 0.00356 AC XY: 2580 AN XY: 723746

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000999

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00450

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74500

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00438

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ExAC AF: 0.00233 AC: 283

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TSC1: BS1, BS2 -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Tuberous sclerosis syndrome Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.23
Dann	Benign	0.58
FATHMM_MKL	Benign	0.024	N
MetaRNN	Benign	0.0053	T;T;T;T
MutationTaster	Benign	1.0	N;N;N;N
Polyphen		0.0	B;B;B;.
GERP RS		-2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs118203507; hg19: chr9-135785870; COSMIC: COSV104404440; COSMIC: COSV104404440;