chr3-30672342-G-A

Position:

chr3-30672342-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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: {Likely_benign=10, Benign=4, not_provided=1, Uncertain_significance=3}. Variant chr3-30672342-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6 linkuse as main transcript	c.1159G>A	p.Val387Met	missense_variant	4/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10 linkuse as main transcript	c.1159G>A	p.Val387Met	missense_variant	4/7	1	NM_003242.6	ENSP00000295754	P1	P37173-1
TGFBR2	ENST00000359013.4 linkuse as main transcript	c.1234G>A	p.Val412Met	missense_variant	5/8	1		ENSP00000351905		P37173-2
TGFBR2	ENST00000672866.1 linkuse as main transcript	n.2755G>A		non_coding_transcript_exon_variant	4/7

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

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2020	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TGFBR2: PP3, BS1 -

Loeys-Dietz syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 17, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2017	- -

Congenital aneurysm of ascending aorta

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 19, 2017

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 11, 2020

- -

Loeys-Dietz syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 19, 2018

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 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). -

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

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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;.

MutationTaster

Benign

1.0

D;D

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