Genetic Variant NM_003242.6:c.454+3139G>A (chr3-30653599-G-A) – 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.454+3139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,066 control chromosomes in the GnomAD database, including 2,082 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 0.15 ( 2082 hom., cov: 31)

Consequence

TGFBR2
NM_003242.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.300

Publications

7 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Loeys-Dietz syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
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=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003242.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TGFBR2	NM_003242.6	MANE Select	c.454+3139G>A	intron	N/A	NP_003233.4
TGFBR2	NM_001407126.1		c.529+3139G>A	intron	N/A	NP_001394055.1
TGFBR2	NM_001407127.1		c.454+3139G>A	intron	N/A	NP_001394056.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TGFBR2	ENST00000295754.10	TSL:1 MANE Select	c.454+3139G>A	intron	N/A	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4	TSL:1	c.529+3139G>A	intron	N/A	ENSP00000351905.4	P37173-2
TGFBR2	ENST00000941789.1		c.454+3139G>A	intron	N/A	ENSP00000611848.1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23523

AN:

151948

Hom.:

2088

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.157

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

GnomAD4 genome

AF:

0.155

AC:

23520

AN:

152066

Hom.:

2082

Cov.:

AF XY:

0.156

AC XY:

11598

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.166

AC:

6862

AN:

41462

American (AMR)

AF:

0.205

AC:

3134

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

391

AN:

3468

East Asian (EAS)

AF:

0.371

AC:

1905

AN:

5138

South Asian (SAS)

AF:

0.189

AC:

912

AN:

4818

European-Finnish (FIN)

AF:

0.112

AC:

1187

AN:

10606

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.125

AC:

8495

AN:

67986

Other (OTH)

AF:

0.158

AC:

334

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1015

2031

3046

4062

5077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.144

Hom.:

204

Bravo

AF:

0.166

Asia WGS

AF:

0.263

AC:

915

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.64

(source)

DANN

Benign

0.64

PhyloP100

-0.30

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over