Genetic Variant TGFBR2:c.*328_*329dupAT (chr3-30691909-T-TTA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_003242.6(TGFBR2):c.*328_*329dupAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.075 ( 1092 hom., cov: 0)

Exomes 𝑓: 0.012 ( 7 hom. )

Consequence

TGFBR2
NM_003242.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.163

Publications

3 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 -10 ACMG points.

BP6

Variant 3-30691909-T-TTA is Benign according to our data. Variant chr3-30691909-T-TTA is described in ClinVar as Benign. ClinVar VariationId is 1231162.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.328_329dupAT		3_prime_UTR_variant	Exon 7 of 7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10 link	c.328_329dupAT		3_prime_UTR_variant	Exon 7 of 7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes

AF:

0.0751

AC:

11064

AN:

147250

Hom.:

1093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.00222

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0152

Gnomad EAS

AF:

0.00668

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.0621

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0582

GnomAD4 exome

AF:

0.0116

AC:

1151

AN:

98988

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

517

AN XY:

49106

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0931

AC:

373

AN:

4008

American (AMR)

AF:

0.0109

AC:

AN:

5216

Ashkenazi Jewish (ASJ)

AF:

0.00910

AC:

AN:

4616

East Asian (EAS)

AF:

0.00886

AC:

107

AN:

12082

South Asian (SAS)

AF:

0.00133

AC:

AN:

6762

European-Finnish (FIN)

AF:

0.00247

AC:

AN:

1620

Middle Eastern (MID)

AF:

0.0220

AC:

AN:

500

European-Non Finnish (NFE)

AF:

0.00732

AC:

420

AN:

57342

Other (OTH)

AF:

0.0187

AC:

128

AN:

6842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.377

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0752

AC:

11071

AN:

147286

Hom.:

1092

Cov.:

AF XY:

0.0725

AC XY:

5200

AN XY:

71712

show subpopulations

African (AFR)

AF:

0.235

AC:

9368

AN:

39854

American (AMR)

AF:

0.0409

AC:

604

AN:

14754

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

AN:

3422

East Asian (EAS)

AF:

0.00670

AC:

AN:

5076

South Asian (SAS)

AF:

0.0126

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.00621

AC:

AN:

9340

Middle Eastern (MID)

AF:

0.0643

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0113

AC:

759

AN:

66944

Other (OTH)

AF:

0.0579

AC:

117

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

403

807

1210

1614

2017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.00983

Hom.:

277

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 25, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-30691909-TTATATATATA-TTATATATATATA

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