rs777529733

Positions:

• chr16-2084657-G-A
• chr16-2084657-G-C
• chr16-2084657-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS2

The NM_000548.5(TSC2):​c.4435G>A​(p.Ala1479Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,446,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1479V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• 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 Benign. Variant got -7 ACMG points.

• 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=0.046156198).
• BP6: Variant 16-2084657-G-A is Benign according to our data. Variant chr16-2084657-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405956.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}. Variant chr16-2084657-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4435G>A	p.Ala1479Thr	missense_variant	34/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4435G>A	p.Ala1479Thr	missense_variant	34/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1446718 Hom.: 0 Cov.: 33 AF XY: 0.00000694 AC XY: 5 AN XY: 720166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2015

- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces alanine with threonine at codon 1479 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2024

The p.A1479T variant (also known as c.4435G>A), located in coding exon 33 of the TSC2 gene, results from a G to A substitution at nucleotide position 4435. The alanine at codon 1479 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	1.3
DANN	Benign	0.62
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.55
Sift	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0050	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.19
MutPred		0.24		Gain of phosphorylation at A1479 (P = 0.0073);.;.;.;.;.;.;Gain of phosphorylation at A1479 (P = 0.0073);.;.;.;.;.;.;.;
MVP		0.99
ClinPred		0.038	T
GERP RS		0.26
Varity_R		0.034
gMVP		0.44

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: COSV99238977; COSMIC: COSV99238977;