3-30644922-A-G

Variant names:

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.263+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,611,264 control chromosomes in the GnomAD database, including 98,950 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 0.35 ( 9561 hom., cov: 32)

Exomes 𝑓: 0.34 ( 89389 hom. )

Consequence

TGFBR2
NM_003242.6 splice_region, intron

Scores

Splicing: ADA: 0.00002644

Clinical Significance

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

Conservation

PhyloP100: -1.23

Publications

49 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=-0.92).

BP6

Variant 3-30644922-A-G is Benign according to our data. Variant chr3-30644922-A-G is described in ClinVar as Benign. ClinVar VariationId is 36867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.263+7A>G		splice_region_variant, intron_variant	Intron 2 of 6	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10 link	c.263+7A>G		splice_region_variant, intron_variant	Intron 2 of 6	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52774

AN:

151882

Hom.:

9569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.255

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.259

Gnomad EAS

AF:

0.687

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.329

GnomAD2 exomes

AF:

0.370

AC:

92790

AN:

250742

AF XY:

0.369

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.694

Gnomad FIN exome

AF:

0.385

Gnomad NFE exome

AF:

0.341

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.344

AC:

501272

AN:

1459262

Hom.:

89389

Cov.:

AF XY:

0.344

AC XY:

249995

AN XY:

726116

show subpopulations

African (AFR)

AF:

0.336

AC:

11228

AN:

33426

American (AMR)

AF:

0.341

AC:

15237

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6612

AN:

26120

East Asian (EAS)

AF:

0.666

AC:

26412

AN:

39666

South Asian (SAS)

AF:

0.362

AC:

31183

AN:

86198

European-Finnish (FIN)

AF:

0.386

AC:

20610

AN:

53388

Middle Eastern (MID)

AF:

0.333

AC:

1919

AN:

5762

European-Non Finnish (NFE)

AF:

0.331

AC:

367232

AN:

1109720

Other (OTH)

AF:

0.346

AC:

20839

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15010

30020

45029

60039

75049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11872

23744

35616

47488

59360

<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:

0.347

AC:

52787

AN:

152002

Hom.:

9561

Cov.:

AF XY:

0.349

AC XY:

25951

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.337

AC:

13964

AN:

41470

American (AMR)

AF:

0.304

AC:

4645

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

897

AN:

3470

East Asian (EAS)

AF:

0.686

AC:

3535

AN:

5152

South Asian (SAS)

AF:

0.367

AC:

1768

AN:

4820

European-Finnish (FIN)

AF:

0.380

AC:

4009

AN:

10554

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22933

AN:

67956

Other (OTH)

AF:

0.329

AC:

694

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1752

3504

5256

7008

8760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.341

Hom.:

34095

Bravo

AF:

0.342

Asia WGS

AF:

0.497

AC:

1731

AN:

3478

EpiCase

AF:

0.322

EpiControl

AF:

0.325

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

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 56% of patients studied by a panel of primary immunodeficiencies. Number of patients: 49. Only high quality variants are reported.

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 01, 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.

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

May 07, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Aug 14, 2021

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

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.

Sep 10, 2021

Genome-Nilou Lab

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

Benign:1

Aug 18, 2011

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

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

-0.92

CADD

Benign

0.054

(source)

DANN

Benign

0.68

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0040

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