rs118203716

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000368.5(TSC1):​c.2626-6_2626-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,350,302 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 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 0.000029 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

TSC1
NM_000368.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.485
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 9-132897613-GAAA-G is Benign according to our data. Variant chr9-132897613-GAAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466092.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr9-132897613-GAAA-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00162 (2014/1246168) while in subpopulation AMR AF= 0.00351 (95/27060). AF 95% confidence interval is 0.00294. There are 0 homozygotes in gnomad4_exome. There are 1009 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 2014 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC1NM_000368.5 linkuse as main transcriptc.2626-6_2626-4del splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000298552.9 NP_000359.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkuse as main transcriptc.2626-6_2626-4del splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_000368.5 ENSP00000298552 P4Q92574-1

Frequencies

GnomAD3 genomes
AF:
0.0000288
AC:
3
AN:
104134
Hom.:
0
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000806
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00162
AC:
2014
AN:
1246168
Hom.:
0
AF XY:
0.00163
AC XY:
1009
AN XY:
619228
show subpopulations
Gnomad4 AFR exome
AF:
0.00233
Gnomad4 AMR exome
AF:
0.00351
Gnomad4 ASJ exome
AF:
0.00294
Gnomad4 EAS exome
AF:
0.00228
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.00357
Gnomad4 NFE exome
AF:
0.00142
Gnomad4 OTH exome
AF:
0.00253
GnomAD4 genome
AF:
0.0000288
AC:
3
AN:
104134
Hom.:
0
Cov.:
0
AF XY:
0.0000412
AC XY:
2
AN XY:
48598
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000809
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthOct 02, 2023This variant causes a deletion of four nucleotides at the -4 position in intron 20 of the TSC1 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 27, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2017- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submittercurationSema4, Sema4May 20, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000; API