9-132897613-GAAAAAAAAAAAA-GAAAAAAAAAAAAAAA

Variant names:

• chr9-132897613-G-GAAA
• rs5901000
• NM_000368.5:c.2626-6_2626-4dupTTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000368.5(TSC1):​c.2626-6_2626-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 0)
  • Exomes 𝑓: 0.047 (171 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: -0.517
• Publications: 7 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 9-132897613-G-GAAA is Benign according to our data. Variant chr9-132897613-G-GAAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365514.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (1377/103970) while in subpopulation AFR AF = 0.0302 (729/24106). AF 95% confidence interval is 0.0284. There are 41 homozygotes in GnomAd4. There are 618 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1377 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2626-6_2626-4dupTTT		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-6_2626-4dupTTT		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-6_2626-4dupTTT		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.2626-4_2626-3insTTT		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-4_2626-3insTTT		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-4_2626-3insTTT		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1380 AN: 103968 Hom.: 42 Cov.: 0

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00139

Gnomad AMR AF: 0.00686

Gnomad ASJ AF: 0.000670

Gnomad EAS AF: 0.00188

Gnomad SAS AF: 0.00636

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00450

Gnomad NFE AF: 0.00971

Gnomad OTH AF: 0.0160

GnomAD2 exomes AF: 0.0565 AC: 5864 AN: 103824 AF XY: 0.0562

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.0651

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.0850

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0526

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0469 AC: 57600 AN: 1229252 Hom.: 171 Cov.: 0 AF XY: 0.0468 AC XY: 28562 AN XY: 610466

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

African (AFR) AF: 0.0306 AC: 849 AN: 27742

American (AMR) AF: 0.0448 AC: 1191 AN: 26606

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 1015 AN: 19776

East Asian (EAS) AF: 0.0377 AC: 1308 AN: 34734

South Asian (SAS) AF: 0.0731 AC: 4645 AN: 63524

European-Finnish (FIN) AF: 0.0370 AC: 1202 AN: 32448

Middle Eastern (MID) AF: 0.0284 AC: 127 AN: 4478

European-Non Finnish (NFE) AF: 0.0464 AC: 45002 AN: 969302

Other (OTH) AF: 0.0446 AC: 2261 AN: 50642

⚠️ 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: 0.0132 AC: 1377 AN: 103970 Hom.: 41 Cov.: 0 AF XY: 0.0127 AC XY: 618 AN XY: 48524

African (AFR) AF: 0.0302 AC: 729 AN: 24106

American (AMR) AF: 0.00665 AC: 66 AN: 9922

Ashkenazi Jewish (ASJ) AF: 0.000670 AC: 2 AN: 2984

East Asian (EAS) AF: 0.00189 AC: 7 AN: 3704

South Asian (SAS) AF: 0.00605 AC: 18 AN: 2974

European-Finnish (FIN) AF: 0.00111 AC: 4 AN: 3616

Middle Eastern (MID) AF: 0.00500 AC: 1 AN: 200

European-Non Finnish (NFE) AF: 0.00970 AC: 527 AN: 54356

Other (OTH) AF: 0.0159 AC: 22 AN: 1386

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Tuberous sclerosis 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Isolated focal cortical dysplasia type II (1)
-	1	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

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;