NM_003238.6:c.199G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_003238.6(TGFB2):c.199G>A(p.Val67Met) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

TGFB2
NM_003238.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 4.36

Variant links:

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29611892).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152242) while in subpopulation NFE AF= 0.000309 (21/68044). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6 link	c.199G>A	p.Val67Met	missense_variant	Exon 1 of 7	ENST00000366930.9	NP_003229.1	P61812-1Q59EG9
TGFB2	NM_001135599.4 link	c.199G>A	p.Val67Met	missense_variant	Exon 1 of 8		NP_001129071.1	P61812-2Q59EG9
TGFB2	NR_138148.2 link	n.1565G>A		non_coding_transcript_exon_variant	Exon 1 of 7
TGFB2	NR_138149.2 link	n.1565G>A		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9 link	c.199G>A	p.Val67Met	missense_variant	Exon 1 of 7	1	NM_003238.6	ENSP00000355897.4		P61812-1
TGFB2	ENST00000366929.4 link	c.199G>A	p.Val67Met	missense_variant	Exon 1 of 8	1		ENSP00000355896.4		P61812-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251318

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000283

AC:

413

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000357

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000158

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4

Uncertain:4

Nov 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 67 of the TGFB2 protein (p.Val67Met). This variant is present in population databases (rs201761868, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TGFB2-related conditions (PMID: 28139901, 29543232). ClinVar contains an entry for this variant (Variation ID: 213839). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFB2 c.199G>A; p.Val67Met variant (rs201761868) is reported in the literature in individuals affected with multiple aneurysms and/or pseudoaneurysm syndrome or thoracic aortic aneurysm/aortic dissection (D'Souza 2017, Weerakkody 2018). This variant is reported in ClinVar (Variation ID: 213839), and is found in the non-Finnish European population with an allele frequency of 0.023% (30/129,078 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.272). Due to limited information, the clinical significance of this variant is uncertain at this time. References: D'Souza RS et al. Clinical and genetic characterization of adult patients presenting with non-syndromic vascular aneurysms and dissections. Int Angiol. 2017 Oct;36(5):417-427. PMID: 28139901. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V67M variant (also known as c.199G>A), located in coding exon 1 of the TGFB2 gene, results from a G to A substitution at nucleotide position 199. The valine at codon 67 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a thoracic aortic aneurysm and dissection (TAAD) cohort (Weerakkody R et al. Genet. Med., 2018 11;20:1414-1422). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 09, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in TGFB2 is predicted to replace valine with methionine at codon 67, p.(Val67Met). The valine residue is highly conserved (100 vertebrates, UCSC), and is located in the TGFb propeptide. There is a small physicochemical difference between valine and methionine. The highest population minor allele frequency in gnomAD v4.1 is 0.04% (418/1,180,054 alleles, 1 homozygote) in the European (non-Finnish) population. This variant has been detected in individuals with aortic aneurysms and one individual with hypermobile Ehlers-Danlos syndrome (PMID: 28139901, 29543232). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.272). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4. -

not provided

Uncertain:2

Apr 19, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual with aneurysm of the descending thoracoabdominal aorta and in an individual with multiple-aneurysms and/or pseudoaneurysm syndromes (MaPS) (PMID: 29543232, 28139901); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22772371, 28139901, 29543232) -

not specified

Uncertain:1

Oct 23, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFB2 c.199G>A (p.Val67Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251318 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Thoracic Aortic Aneurysms And Dissections phenotype (2.5e-05), strongly suggesting that the variant is benign. c.199G>A has been reported in the literature in individuals affected with Thoracic Aortic Aneurysms And Dissections (Boileau_2012, Weerakkody_2018) or multiple-aneurysms and/or pseudoaneurysm syndromes (DSouza_2017). These reports do not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29543232, 22772371, 28139901). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Ehlers-Danlos syndrome

Uncertain:1

Jan 28, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.99

D;D

Vest4

0.35

MVP

0.66

MPC

1.7

ClinPred

0.85

GERP RS

5.5

Varity_R

0.62

gMVP

0.62

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