rs1287273870

Variant names:

• chr16-2076147-G-A
• rs1287273870
• NM_000548.5:c.2719G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2076147-G-A
• chr16-2076147-G-C
• chr16-2076147-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000548.5(TSC2):​c.2719G>A​(p.Asp907Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D907G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92
• 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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 37 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33000213).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.2719G>A	p.Asp907Asn	missense	Exon 24 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2719G>A	p.Asp907Asn	missense	Exon 24 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2719G>A	p.Asp907Asn	missense	Exon 24 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2719G>A	p.Asp907Asn	missense	Exon 24 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2719G>A	p.Asp907Asn	missense	Exon 24 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2719G>A	p.Asp907Asn	missense	Exon 24 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 30, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D907N variant (also known as c.2719G>A), located in coding exon 23 of the TSC2 gene, results from a G to A substitution at nucleotide position 2719. The aspartic acid at codon 907 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	30
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.69	N
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.15	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.29		Gain of MoRF binding (P = 0.0471)
MVP		0.91
ClinPred		0.83	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.52
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1287273870; hg19: chr16-2126148;