9-132891603-TA-T

Variant names:

• chr9-132891603-TA-T
• rs60000611
• NM_000368.5:c.*4631delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000368.5(TSC1):​c.*4631delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 233,420 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: TSC1 NM_000368.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 9-132891603-TA-T is Benign according to our data. Variant chr9-132891603-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 365388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00363 (553/152186) while in subpopulation AFR AF = 0.0114 (475/41524). AF 95% confidence interval is 0.0106. There are 6 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.*4631delT		3_prime_UTR_variant	Exon 23 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.*4631delT		3_prime_UTR_variant	Exon 23 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.*4631delT		3_prime_UTR_variant	Exon 24 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152068 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00126 AC: 102 AN: 81234 Hom.: 0 Cov.: 0 AF XY: 0.00112 AC XY: 42 AN XY: 37384

African (AFR) AF: 0.0157 AC: 61 AN: 3890

American (AMR) AF: 0.000803 AC: 2 AN: 2490

Ashkenazi Jewish (ASJ) AF: 0.00254 AC: 13 AN: 5116

East Asian (EAS) AF: 0.00 AC: 0 AN: 11368

South Asian (SAS) AF: 0.00 AC: 0 AN: 702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 476

Middle Eastern (MID) AF: 0.00408 AC: 2 AN: 490

European-Non Finnish (NFE) AF: 0.000320 AC: 16 AN: 49938

Other (OTH) AF: 0.00118 AC: 8 AN: 6764

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152186 Hom.: 6 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74414

African (AFR) AF: 0.0114 AC: 475 AN: 41524

American (AMR) AF: 0.00242 AC: 37 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67998

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00396

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

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Other links and lift over

dbSNP: rs60000611; hg19: chr9-135766990;