16-2084657-G-T

Position:

• chr16-2084657-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_000548.5(TSC2):​c.4435G>T​(p.Ala1479Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1479T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2084657-GCC-GTTAAA is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.049221396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4435G>T	p.Ala1479Ser	missense_variant	34/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4435G>T	p.Ala1479Ser	missense_variant	34/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446718 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 720166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000829 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	0.37
DANN	Benign	0.62
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.093	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.049	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.52	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.56
Sift	Benign	0.85	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.79	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.025	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.21
MutPred		0.24		Gain of phosphorylation at A1479 (P = 0.0062);.;.;.;.;.;.;Gain of phosphorylation at A1479 (P = 0.0062);.;.;.;.;.;.;.;
MVP		0.99
ClinPred		0.041	T
GERP RS		0.26
Varity_R		0.040
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs777529733; hg19: chr16-2134658; COSMIC: COSV51910928; COSMIC: COSV51910928;