3-30691909-TTATATATATA-TTATATATATATATA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003242.6(TGFBR2):c.*326_*329dupATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

TGFBR2
NM_003242.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B: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 -9 ACMG points.

BP6

Variant 3-30691909-T-TTATA is Benign according to our data. Variant chr3-30691909-T-TTATA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344669.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00272 (401/147342) while in subpopulation AFR AF = 0.00852 (340/39884). AF 95% confidence interval is 0.00778. There are 1 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 401 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.326_329dupATAT		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.326_329dupATAT		3_prime_UTR_variant	Exon 7 of 7	1	NM_003242.6	ENSP00000295754.5

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

399

AN:

147306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00849

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00102

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00196

Gnomad SAS

AF:

0.00170

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000343

Gnomad OTH

AF:

0.00249

GnomAD4 exome

AF:

0.000390

AC:

AN:

100082

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

AN XY:

49616

show subpopulations

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

African (AFR)

AF:

0.00271

AC:

AN:

4054

American (AMR)

AF:

0.00

AC:

AN:

5244

Ashkenazi Jewish (ASJ)

AF:

0.000213

AC:

AN:

4698

East Asian (EAS)

AF:

0.000162

AC:

AN:

12362

South Asian (SAS)

AF:

0.000443

AC:

AN:

6772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1620

Middle Eastern (MID)

AF:

0.00394

AC:

AN:

508

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

57884

Other (OTH)

AF:

0.00101

AC:

AN:

6940

⚠️ 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: 0.352

Heterozygous variant carriers

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:

0.00272

AC:

401

AN:

147342

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

181

AN XY:

71732

show subpopulations

African (AFR)

AF:

0.00852

AC:

340

AN:

39884

American (AMR)

AF:

0.00102

AC:

AN:

14760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00197

AC:

AN:

5076

South Asian (SAS)

AF:

0.00171

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000343

AC:

AN:

66958

Other (OTH)

AF:

0.00247

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000112

Hom.:

277

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Marfan syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Loeys-Dietz syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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