rs3049911

Positions:

• chr9-132897613-G-GAAAA
• chr9-132897613-G-GAAAAA
• chr9-132897613-GAAA-G
• chr9-132897613-G-GAAAAAAA
• chr9-132897613-GAAAAAA-G
• chr9-132897613-GAAAA-G
• chr9-132897613-G-GAAA
• chr9-132897613-G-GA
• chr9-132897613-G-GAA
• chr9-132897613-GA-G
• chr9-132897613-GAA-G
• chr9-132897613-GAAAAA-G
• chr9-132897613-G-GAAAAAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000368.5(TSC1):​c.2626-7_2626-4dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (10 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.517

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 9-132897613-G-GAAAA is Benign according to our data. Variant chr9-132897613-G-GAAAA is described in ClinVar as [Likely_benign]. Clinvar id is 1692398.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00383 (4777/1247732) while in subpopulation SAS AF= 0.0117 (754/64696). AF 95% confidence interval is 0.011. There are 10 homozygotes in gnomad4_exome. There are 2467 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2626-7_2626-4dupTTTT		splice_region_variant, intron_variant		ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2626-7_2626-4dupTTTT		splice_region_variant, intron_variant		1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2626-7_2626-4dupTTTT		splice_region_variant, intron_variant		3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 14 AN: 104094 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000276

Gnomad MID AF: 0.00450

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00383 AC: 4777 AN: 1247732 Hom.: 10 Cov.: 0 AF XY: 0.00398 AC XY: 2467 AN XY: 619954

Gnomad4 AFR exome AF: 0.00366

Gnomad4 AMR exome AF: 0.00744

Gnomad4 ASJ exome AF: 0.00567

Gnomad4 EAS exome AF: 0.00480

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.00416

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.000134 AC: 14 AN: 104094 Hom.: 1 Cov.: 0 AF XY: 0.000144 AC XY: 7 AN XY: 48580

Gnomad4 AFR AF: 0.0000829

Gnomad4 AMR AF: 0.000101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000276

Gnomad4 NFE AF: 0.000165

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;