rs148665451

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_003242.6(TGFBR2):c.985G>A(p.Ala329Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A329V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 1.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003242.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0606305).

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6 linkuse as main transcript	c.985G>A	p.Ala329Thr	missense_variant	4/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10 linkuse as main transcript	c.985G>A	p.Ala329Thr	missense_variant	4/7	1	NM_003242.6	P1	P37173-1
TGFBR2	ENST00000359013.4 linkuse as main transcript	c.1060G>A	p.Ala354Thr	missense_variant	5/8	1			P37173-2
TGFBR2	ENST00000672866.1 linkuse as main transcript	n.2581G>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

250970

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000814

AC:

119

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2021	The TGFBR2 c.985G>A; p.Ala329Thr variant (rs149425237) has been identified in multiple individuals included in cohorts of Loeys-Dietz syndrome patients or thoracic aortic aneurysms and dissections (TAAD; Barnett 2011, Frischmeyer-Guerrerio 2013, Jani 2020, Loeys 2006). However, this variant is found in the general population with an allele frequency in Ashkenazi Jewish individuals of 0.19% (20/10,346 alleles) in the Genome Aggregation Database. The alanine at codon 329 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.59). Based on the available information, the clinical significance of this variant is uncertain. References: Barnett et al. Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? Eur J Hum Genet. 2011 Jun;19(6):624-33. PMID: 21267002 Frischmeyer-Guerrerio et al. TGFß receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med. 2013 Jul 24;5(195):195ra94. PMID: 23884466 Jani et al. Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation. J Med Genet. 2020 Oct;57(10):699-707. PMID: 32152251 Loeys et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. PMID: 16928994 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	This variant is associated with the following publications: (PMID: 21267002, 16928994, 24055113, 25637381, 23884466, 17061023, 30739908, 32152251) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TGFBR2: BS2 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Loeys-Dietz syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Marfan syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

TGFBR2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.040

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.061

T;T

MetaSVM

Uncertain

-0.040

MutationAssessor

Benign

0.57

N;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.85

N;N

REVEL

Uncertain

0.59

Sift

Benign

0.45

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.10

B;.

Vest4

0.28

MVP

0.99

MPC

0.53

ClinPred

0.023

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.38

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

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