rs11466512

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003242.6(TGFBR2):c.455-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,682 control chromosomes in the GnomAD database, including 77,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5767 hom., cov: 33)

Exomes 𝑓: 0.31 ( 71418 hom. )

Consequence

TGFBR2
NM_003242.6 splice_region, intron

Scores

Splicing: ADA: 0.0003021

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.564

Publications

38 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 3-30671634-T-A is Benign according to our data. Variant chr3-30671634-T-A is described in ClinVar as Benign. ClinVar VariationId is 44658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.455-4T>A		splice_region_variant, intron_variant	Intron 3 of 6	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.455-4T>A		splice_region_variant, intron_variant	Intron 3 of 6	1	NM_003242.6	ENSP00000295754.5		P37173-1

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40090

AN:

152018

Hom.:

5768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.354

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.276

GnomAD2 exomes

AF:

0.300

AC:

75434

AN:

251114

AF XY:

0.293

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.443

Gnomad ASJ exome

AF:

0.201

Gnomad EAS exome

AF:

0.317

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.297

GnomAD4 exome

AF:

0.308

AC:

450865

AN:

1461546

Hom.:

71418

Cov.:

AF XY:

0.305

AC XY:

221547

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.148

AC:

4941

AN:

33476

American (AMR)

AF:

0.438

AC:

19578

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

5385

AN:

26132

East Asian (EAS)

AF:

0.324

AC:

12872

AN:

39686

South Asian (SAS)

AF:

0.218

AC:

18815

AN:

86252

European-Finnish (FIN)

AF:

0.287

AC:

15341

AN:

53408

Middle Eastern (MID)

AF:

0.195

AC:

1127

AN:

5768

European-Non Finnish (NFE)

AF:

0.320

AC:

355263

AN:

1111720

Other (OTH)

AF:

0.291

AC:

17543

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16806

33613

50419

67226

84032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11596

23192

34788

46384

57980

<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:

0.264

AC:

40103

AN:

152136

Hom.:

5767

Cov.:

AF XY:

0.260

AC XY:

19315

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.153

AC:

6359

AN:

41518

American (AMR)

AF:

0.354

AC:

5405

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

740

AN:

3464

East Asian (EAS)

AF:

0.316

AC:

1635

AN:

5166

South Asian (SAS)

AF:

0.226

AC:

1089

AN:

4826

European-Finnish (FIN)

AF:

0.281

AC:

2974

AN:

10580

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20863

AN:

67976

Other (OTH)

AF:

0.275

AC:

582

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1483

2967

4450

5934

7417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.250

Hom.:

1704

Bravo

AF:

0.270

Asia WGS

AF:

0.264

AC:

920

AN:

3478

EpiCase

AF:

0.300

EpiControl

AF:

0.305

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2012

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. -

Sep 19, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

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:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

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

- -

May 09, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Loeys-Dietz syndrome 2

Benign:1

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. -

Cardiovascular phenotype

Benign:1

Feb 10, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Thoracic aortic aneurysm

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.3

(source)

DANN

Benign

0.53

PhyloP100

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.022

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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