3-30672342-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_003242.6(TGFBR2):c.1159G>A(p.Val387Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,764 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:15O:1

Conservation

PhyloP100: 8.05

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 Benign. Variant got -9 ACMG points.

PM1

In a domain Protein kinase (size 300) in uniprot entity TGFR2_HUMAN there are 34 pathogenic changes around while only 5 benign (87%) in NM_003242.6

BP4

Computational evidence support a benign effect (MetaRNN=0.21082172).

BP6

Variant 3-30672342-G-A is Benign according to our data. Variant chr3-30672342-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=4, Likely_benign=10, not_provided=1}. Variant chr3-30672342-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (172/152290) while in subpopulation NFE AF= 0.00194 (132/68022). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.1159G>A	p.Val387Met	missense_variant	Exon 4 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFBR2	ENST00000295754.10 link	c.1159G>A	p.Val387Met	missense_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4 link	c.1234G>A	p.Val412Met	missense_variant	Exon 5 of 8	1		ENSP00000351905.4	P37173-2
TGFBR2	ENST00000672866.1 link	n.2755G>A		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00103

AC:

259

AN:

250480

Hom.:

AF XY:

0.00101

AC XY:

137

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000301

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00177

AC:

2582

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1216

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.000461

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00214

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152290

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00194

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00114

AC:

139

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:15Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:5

Jun 18, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR2: PP3, BS1 -

Aug 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32560555, 27879313, 26332594, 26017485, 24941995, 25116393, 16791849, 25637381, 18781618, 23074336, 16571647, 21524434, 17319955, 16928994, 11212236, 24055113) -

Mar 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Sep 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital aneurysm of ascending aorta

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2

Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR2 NM_003242 exon 4 p.Val387Met (c.1234G>A): This variant has been reported in the literature in at least 1 individual with suspicion of a syndromic aortopathy; however, the authors of this study suggested that this variant is likely benign (Lerner-Ellis 2014 PMID:24793577). In addition, this variant is present in 0.1% (251/125876) of European individuals, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs35766612). This variant is present in ClinVar (Variation ID:44651). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2

Uncertain:1

Sep 19, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR2 NM_003242.5 exon 4 p.Val387Met (c.1234G>A): This variant has been reported in the literature in at least 1 individual with suspicion of a syndromic aortopathy; however, the authors of this study suggested that this variant is likely benign (Lerner-Ellis 2014 PMID:24793577). In addition, this variant is present in 0.1% (251/125876) of European individuals, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs35766612). This variant is present in ClinVar (Variation ID:44651). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Marfan syndrome

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Dec 11, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 2

Benign:1

Mar 19, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

TGFBR2-related disorder

Benign:1

Jul 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Thoracic aortic aneurysm;C0729233:Thoracic aortic dissection;C2697932:Loeys-Dietz syndrome

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

1.5

L;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.3

N;N

REVEL

Pathogenic

0.79

Sift

Benign

0.076

T;T

Sift4G

Benign

0.15

T;T

Polyphen

1.0

D;.

Vest4

0.84

MVP

0.95

MPC

1.4

ClinPred

0.026

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.79

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