9-132897613-G-GGA

Variant names:

• chr9-132897613-G-GGA
• rs1554813651
• NM_000368.5:c.2626-4_2626-3insTC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000368.5(TSC1):​c.2626-4_2626-3insTC 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TSC1 NM_000368.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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: 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 -1 ACMG points.

• BP6: Variant 9-132897613-G-GGA is Benign according to our data. Variant chr9-132897613-G-GGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466090.

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.2626-4_2626-3insTC		splice_region intron	N/A	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2626-4_2626-3insTC		splice_region intron	N/A	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2626-4_2626-3insTC		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_2626-3insTC		splice_region intron	N/A	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2626-4_2626-3insTC		splice_region intron	N/A	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2626-4_2626-3insTC		splice_region intron	N/A	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0000288 AC: 3 AN: 104138 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000830

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: 0.0000191 AC: 24 AN: 1254010 Hom.: 0 Cov.: 0 AF XY: 0.0000241 AC XY: 15 AN XY: 623266

⚠️ 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: 28216

American (AMR) AF: 0.0000367 AC: 1 AN: 27256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20218

East Asian (EAS) AF: 0.00 AC: 0 AN: 35462

South Asian (SAS) AF: 0.000198 AC: 13 AN: 65660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.0000101 AC: 10 AN: 987716

Other (OTH) AF: 0.00 AC: 0 AN: 51766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000977588), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000288 AC: 3 AN: 104138 Hom.: 0 Cov.: 0 AF XY: 0.0000206 AC XY: 1 AN XY: 48580

African (AFR) AF: 0.0000830 AC: 2 AN: 24100

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: 3722

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: 54482

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

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Tuberous sclerosis 1 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52

Splicing

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

Other links and lift over

dbSNP: rs1554813651; hg19: chr9-135773000;