rs2228363

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003243.5(TGFBR3):c.2329C>T(p.Pro777Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0102 in 1,613,536 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 104 hom. )

Consequence

TGFBR3
NM_003243.5 missense, splice_region

Scores

Splicing: ADA: 0.08694

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

TGFBR3 (HGNC:11774): (transforming growth factor beta receptor 3) This locus encodes the transforming growth factor (TGF)-beta type III receptor. The encoded receptor is a membrane proteoglycan that often functions as a co-receptor with other TGF-beta receptor superfamily members. Ectodomain shedding produces soluble TGFBR3, which may inhibit TGFB signaling. Decreased expression of this receptor has been observed in various cancers. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[provided by RefSeq, Sep 2010]

TGFBR3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006033629).

BP6

Variant 1-91698089-G-A is Benign according to our data. Variant chr1-91698089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 547818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1042 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR3	NM_003243.5 linkuse as main transcript	c.2329C>T	p.Pro777Ser	missense_variant, splice_region_variant	15/17	ENST00000212355.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR3	ENST00000212355.9 linkuse as main transcript	c.2329C>T	p.Pro777Ser	missense_variant, splice_region_variant	15/17	1	NM_003243.5	P3	Q03167-1

Frequencies

GnomAD3 genomes

AF:

0.00685

AC:

1042

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00667

AC:

1677

AN:

251420

Hom.:

AF XY:

0.00653

AC XY:

888

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.00443

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.0105

AC:

15347

AN:

1461252

Hom.:

104

Cov.:

AF XY:

0.0103

AC XY:

7489

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.00485

Gnomad4 NFE exome

AF:

0.0126

Gnomad4 OTH exome

AF:

0.00977

GnomAD4 genome

AF:

0.00684

AC:

1042

AN:

152284

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

470

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00699

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00663

AC:

805

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TGFBR3: BP4, BS1, BS2 -

TGFBR3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.058

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.63

T;.;.;T

MetaRNN

Benign

0.0060

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

N;.;N;.

MutationTaster

Benign

0.88

D;D;D;D

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.39

N;N;N;N

REVEL

Benign

0.065

Sift

Benign

0.45

T;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.72

MVP

0.55

MPC

0.23

ClinPred

0.010

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.086

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.087

dbscSNV1_RF

Benign

0.21

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over