NM_000548.5:c.3377A>T

Variant names:

• chr16-2079649-A-T
• rs397514945
• NM_000548.5:c.3377A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000548.5(TSC2):​c.3377A>T​(p.Asp1126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000637 in 1,601,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D1126N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 2.48
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 33 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.25961027).
• BP6: Variant 16-2079649-A-T is Benign according to our data. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927. Variant chr16-2079649-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64927.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3377A>T	p.Asp1126Val	missense_variant	Exon 29 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3377A>T	p.Asp1126Val	missense_variant	Exon 29 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000935 AC: 21 AN: 224512 AF XY: 0.000123

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000669 AC: 97 AN: 1449440 Hom.: 0 Cov.: 32 AF XY: 0.0000583 AC XY: 42 AN XY: 719950

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 43232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 84554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5166

European-Non Finnish (NFE) AF: 0.0000831 AC: 92 AN: 1107188

Other (OTH) AF: 0.0000836 AC: 5 AN: 59782

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000159 AC: 19

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Tuberous sclerosis syndrome Uncertain:1 Other:1

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with valine at codon 1126 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 been identified in 23/255854 chromosomes 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. -

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

not specified Benign:1

Oct 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.3377A>T (p.Asp1126Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 224512 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.91 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05). To our knowledge, no occurrence of c.3377A>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 64927). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Sep 27, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24770934, 23514105) -

Hereditary cancer-predisposing syndrome Benign:1

Oct 02, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.7	L;.;.;.;.;.;.;.;.;L;.;.;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.018	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.88	P;.;.;.;B;P;.;.;B;B;.;.;.;.;.
Vest4		0.57
MVP		0.98
ClinPred		0.12	T
GERP RS		3.6
Varity_R		0.17
gMVP		0.30
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs397514945; hg19: chr16-2129650;