NM_000368.5:c.2626-8_2626-4dupTTTTT

Variant names:

• chr9-132897613-G-GAAAAA
• rs5901000
• NM_000368.5:c.2626-8_2626-4dupTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000368.5(TSC1):​c.2626-8_2626-4dupTTTTT 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.517
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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 -2 ACMG points.

• BP6: Variant 9-132897613-G-GAAAAA is Benign according to our data. Variant chr9-132897613-G-GAAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1692399.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-8_2626-4dupTTTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.00000960 AC: 1 AN: 104126 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000184

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000591 AC: 740 AN: 1252702 Hom.: 2 Cov.: 0 AF XY: 0.000604 AC XY: 376 AN XY: 622558

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

African (AFR) AF: 0.000461 AC: 13 AN: 28194

American (AMR) AF: 0.00103 AC: 28 AN: 27210

Ashkenazi Jewish (ASJ) AF: 0.000792 AC: 16 AN: 20194

East Asian (EAS) AF: 0.000989 AC: 35 AN: 35402

South Asian (SAS) AF: 0.00209 AC: 137 AN: 65406

European-Finnish (FIN) AF: 0.000604 AC: 20 AN: 33126

Middle Eastern (MID) AF: 0.000438 AC: 2 AN: 4562

European-Non Finnish (NFE) AF: 0.000457 AC: 451 AN: 986902

Other (OTH) AF: 0.000735 AC: 38 AN: 51706

⚠️ 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 AF: 0.00000960 AC: 1 AN: 104126 Hom.: 0 Cov.: 0 AF XY: 0.0000206 AC XY: 1 AN XY: 48574

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

African (AFR) AF: 0.00 AC: 0 AN: 24098

American (AMR) AF: 0.00 AC: 0 AN: 9916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2992

East Asian (EAS) AF: 0.00 AC: 0 AN: 3720

South Asian (SAS) AF: 0.00 AC: 0 AN: 2988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54474

Other (OTH) AF: 0.00 AC: 0 AN: 1374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs5901000; hg19: chr9-135773000;