chr1-218442109-A-C

Variant names:

Variant summary

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

The NM_003238.6(TGFB2):c.*747A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,828 control chromosomes in the GnomAD database, including 11,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11651 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

TGFB2
NM_003238.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.110

Publications

36 publications found

Variant links:

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Loeys-Dietz syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

TGFB2 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=-0.57).

BP6

Variant 1-218442109-A-C is Benign according to our data. Variant chr1-218442109-A-C is described in ClinVar as Benign. ClinVar VariationId is 295502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6 link	c.*747A>C	3_prime_UTR_variant	Exon 7 of 7	ENST00000366930.9	NP_003229.1	P61812-1Q59EG9
TGFB2	NR_138148.2 link	n.3243A>C	non_coding_transcript_exon_variant	Exon 7 of 7
TGFB2	NR_138149.2 link	n.3327A>C	non_coding_transcript_exon_variant	Exon 8 of 8
TGFB2	NM_001135599.4 link	c.*747A>C	3_prime_UTR_variant	Exon 8 of 8		NP_001129071.1	P61812-2Q59EG9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFB2	ENST00000366930.9 link	c.*747A>C	3_prime_UTR_variant	Exon 7 of 7	1	NM_003238.6	ENSP00000355897.4	P61812-1
TGFB2	ENST00000366929.4 link	c.*747A>C	3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000355896.4	P61812-2
TGFB2	ENST00000479322.1 link	n.1476A>C	non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57031

AN:

151708

Hom.:

11628

Cov.:

show subpopulations

Gnomad AFR

AF:

0.467

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.324

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.369

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.376

AC:

57099

AN:

151826

Hom.:

11651

Cov.:

AF XY:

0.381

AC XY:

28285

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.467

AC:

19341

AN:

41424

American (AMR)

AF:

0.474

AC:

7226

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

1124

AN:

3464

East Asian (EAS)

AF:

0.717

AC:

3705

AN:

5168

South Asian (SAS)

AF:

0.371

AC:

1788

AN:

4818

European-Finnish (FIN)

AF:

0.319

AC:

3351

AN:

10508

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19352

AN:

67868

Other (OTH)

AF:

0.372

AC:

786

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1770

3540

5310

7080

8850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.333

Hom.:

13605

Bravo

AF:

0.395

Asia WGS

AF:

0.492

AC:

1714

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.11

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over