rs777386691

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-132897614-A-G
• chr9-132897614-A-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000368.5(TSC1):​c.2626-4T>C variant causes a splice region, 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Scores: Splicing: ADA: 0.000009526
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-132897614-A-G is Benign according to our data. Variant chr9-132897614-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 9 AD gene.

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>C		splice_region intron	N/A	NP_000359.1
	TSC1	NM_001406592.1		c.2626-4T>C		splice_region intron	N/A	NP_001393521.1
	TSC1	NM_001406593.1		c.2626-4T>C		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>C		splice_region intron	N/A	ENSP00000298552.3
	TSC1	ENST00000490179.4	TSL:3	c.2626-4T>C		splice_region intron	N/A	ENSP00000495533.2
	TSC1	ENST00000643875.1		c.2626-4T>C		splice_region intron	N/A	ENSP00000495158.1

Frequencies

GnomAD3 genomes AF: 0.000280 AC: 9 AN: 32118 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000455

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000212

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.168 AC: 10505 AN: 62494 AF XY: 0.176

Gnomad AFR exome AF: 0.0721

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.0775

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.0000290 AC: 15 AN: 516502 Hom.: 0 Cov.: 0 AF XY: 0.0000194 AC XY: 5 AN XY: 257984

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

African (AFR) AF: 0.000521 AC: 3 AN: 5754

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 17180

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

European-Non Finnish (NFE) AF: 0.0000277 AC: 11 AN: 397650

Other (OTH) AF: 0.00 AC: 0 AN: 20270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000710056), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000280 AC: 9 AN: 32118 Hom.: 0 Cov.: 0 AF XY: 0.000197 AC XY: 3 AN XY: 15220

African (AFR) AF: 0.000300 AC: 5 AN: 16662

American (AMR) AF: 0.000455 AC: 1 AN: 2200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 284

East Asian (EAS) AF: 0.00119 AC: 1 AN: 842

South Asian (SAS) AF: 0.00 AC: 0 AN: 512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 62

European-Non Finnish (NFE) AF: 0.000212 AC: 2 AN: 9424

Other (OTH) AF: 0.00 AC: 0 AN: 364

Alfa AF: 0.0000342 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Benign:3

Apr 28, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis syndrome Benign:1

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Feb 18, 2021

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-0.52
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000095
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs777386691; hg19: chr9-135773001;