9-132897614-A-T

Variant names:

• chr9-132897614-A-T
• rs777386691
• NM_000368.5:c.2626-4T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000368.5(TSC1):​c.2626-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001104
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.517
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-132897614-A-T is Benign according to our data. Variant chr9-132897614-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 747974.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2626-4T>A		splice_region intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2626-4T>A		splice_region intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2626-4T>A		splice_region intron	N/A	NP_001393522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-4T>A		splice_region intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2626-4T>A		splice_region intron	N/A	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2626-4T>A		splice_region intron	N/A	ENSP00000495158.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000310 AC: 16 AN: 516482 Hom.: 0 Cov.: 0 AF XY: 0.0000349 AC XY: 9 AN XY: 257972

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 5754

American (AMR) AF: 0.00 AC: 0 AN: 12354

Ashkenazi Jewish (ASJ) AF: 0.000202 AC: 2 AN: 9888

East Asian (EAS) AF: 0.0000780 AC: 1 AN: 12816

South Asian (SAS) AF: 0.00 AC: 0 AN: 38926

European-Finnish (FIN) AF: 0.0000582 AC: 1 AN: 17178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1664

European-Non Finnish (NFE) AF: 0.0000302 AC: 12 AN: 397638

Other (OTH) AF: 0.00 AC: 0 AN: 20264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Benign:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0020
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: rs777386691; hg19: chr9-135773001;