NM_003242.6:c.999A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003242.6(TGFBR2):c.999A>G(p.Leu333Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,610 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 143 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 130 hom. )

Consequence

TGFBR2
NM_003242.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.906

Publications

6 publications found

Variant links:

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

TGFBR2 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Loeys-Dietz syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
Loeys-Dietz syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TGFBR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 3-30672182-A-G is Benign according to our data. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-30672182-A-G is described in CliVar as Benign. Clinvar id is 44661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.906 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.999A>G	p.Leu333Leu	synonymous_variant	Exon 4 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10 link	c.999A>G	p.Leu333Leu	synonymous_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5		P37173-1

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3553

AN:

152156

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00636

AC:

1596

AN:

251032

AF XY:

0.00469

show subpopulations

Gnomad AFR exome

AF:

0.0836

Gnomad AMR exome

AF:

0.00414

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000450

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00262

AC:

3832

AN:

1461336

Hom.:

130

Cov.:

AF XY:

0.00229

AC XY:

1665

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.0862

AC:

2887

AN:

33474

American (AMR)

AF:

0.00499

AC:

223

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000274

AC:

304

AN:

1111512

Other (OTH)

AF:

0.00581

AC:

351

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

266

532

799

1065

1331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0234

AC:

3561

AN:

152274

Hom.:

143

Cov.:

AF XY:

0.0227

AC XY:

1687

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0796

AC:

3307

AN:

41530

American (AMR)

AF:

0.0127

AC:

195

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68034

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

177

354

531

708

885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0278

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:5

Sep 09, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 19, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 17, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 07, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.999A>G variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. However, these predictions are not confirmed by experimental studies. This variant is found in 926/121218 control chromosomes (including 32 homozygotes) at a frequency of 0.0076391, which is about 1630 times greater than the maximal expected frequency of a pathogenic allele (0.0000047) in this gene, suggesting this variant is benign. In addition, multiple clinical laboratories classified this variant as benign. Taken together, this variant has been classified as Benign. -

Loeys-Dietz syndrome 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Marfan syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Feb 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.15

(source)

DANN

Benign

0.56

PhyloP100

-0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over