16-2048008-A-T

Variant names:

• chr16-2048008-A-T
• rs886051785
• NM_000548.5:c.-87A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_000548.5(TSC2):​c.-87A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,333,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: TSC2 NM_000548.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.490
• Publications: 1 publications found

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

NTHL1 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• NTHL1-deficiency tumor predisposition syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• meningioma

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.-87A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 42	ENST00000219476.9	NP_000539.2
TSC2	NM_000548.5	c.-87A>T		5_prime_UTR_variant	Exon 1 of 42	ENST00000219476.9	NP_000539.2
NTHL1	NM_002528.7	c.-185T>A		upstream_gene_variant		ENST00000651570.2	NP_002519.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.-87A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 42	5	NM_000548.5	ENSP00000219476.3
TSC2	ENST00000219476.9	c.-87A>T		5_prime_UTR_variant	Exon 1 of 42	5	NM_000548.5	ENSP00000219476.3
NTHL1	ENST00000651570.2	c.-185T>A		upstream_gene_variant			NM_002528.7	ENSP00000498421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1333728 Hom.: 0 Cov.: 31 AF XY: 0.00000459 AC XY: 3 AN XY: 653016

African (AFR) AF: 0.0000352 AC: 1 AN: 28380

American (AMR) AF: 0.00 AC: 0 AN: 30672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22262

East Asian (EAS) AF: 0.00 AC: 0 AN: 33608

South Asian (SAS) AF: 0.00 AC: 0 AN: 72352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5352

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1053260

Other (OTH) AF: 0.00 AC: 0 AN: 55534

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.49
PromoterAI		0.13	Neutral
Mutation Taster		=297/3	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

Other links and lift over

dbSNP: rs886051785; hg19: chr16-2098009;