Genetic Variant TGFBR2:c.95-2733C>T (chr3-30642014-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003242.6(TGFBR2):c.95-2733C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 151,916 control chromosomes in the GnomAD database, including 5,521 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5521 hom., cov: 31)

Consequence

TGFBR2
NM_003242.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.242

Publications

14 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.95-2733C>T		intron_variant	Intron 1 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.95-2733C>T		intron_variant	Intron 1 of 6	1	NM_003242.6	ENSP00000295754.5		P37173-1

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40048

AN:

151798

Hom.:

5519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.0314

Gnomad SAS

AF:

0.276

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.264

AC:

40075

AN:

151916

Hom.:

5521

Cov.:

AF XY:

0.263

AC XY:

19494

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.218

AC:

9017

AN:

41412

American (AMR)

AF:

0.284

AC:

4332

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1499

AN:

3470

East Asian (EAS)

AF:

0.0319

AC:

165

AN:

5174

South Asian (SAS)

AF:

0.277

AC:

1332

AN:

4802

European-Finnish (FIN)

AF:

0.269

AC:

2829

AN:

10536

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.294

AC:

19959

AN:

67956

Other (OTH)

AF:

0.294

AC:

620

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1476

2951

4427

5902

7378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.287

Hom.:

27415

Bravo

AF:

0.263

Asia WGS

AF:

0.163

AC:

568

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.9

(source)

DANN

Benign

0.59

PhyloP100

0.24

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over