rs1060503192

Positions:

• chr9-132897613-G-A
• chr9-132897613-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000368.5(TSC1):​c.2626-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 14)
  • Exomes 𝑓: 0.017 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002151
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.387

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-132897613-G-A is Benign according to our data. Variant chr9-132897613-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411211.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=3}. Variant chr9-132897613-G-A is described in Lovd as [Likely_benign]. Variant chr9-132897613-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00603 (626/103884) while in subpopulation EAS AF= 0.00756 (28/3706). AF 95% confidence interval is 0.00544. There are 0 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 14. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2626-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 624 AN: 103884 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00552

Gnomad AMR AF: 0.00606

Gnomad ASJ AF: 0.00569

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.00469

Gnomad FIN AF: 0.00719

Gnomad MID AF: 0.00450

Gnomad NFE AF: 0.00583

Gnomad OTH AF: 0.00655

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0173 AC: 21610 AN: 1245630 Hom.: 15 Cov.: 27 AF XY: 0.0187 AC XY: 11567 AN XY: 618726

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0385

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.0484

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.00603 AC: 626 AN: 103884 Hom.: 0 Cov.: 14 AF XY: 0.00582 AC XY: 282 AN XY: 48488

Gnomad4 AFR AF: 0.00625

Gnomad4 AMR AF: 0.00616

Gnomad4 ASJ AF: 0.00569

Gnomad4 EAS AF: 0.00756

Gnomad4 SAS AF: 0.00471

Gnomad4 FIN AF: 0.00719

Gnomad4 NFE AF: 0.00583

Gnomad4 OTH AF: 0.00649

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TSC1: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

TSC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.77
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.098
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: rs1060503192; hg19: chr9-135773000;