rs201761868
Positions:
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
NM_003238.6 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 4.36
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]
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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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB2 | NM_003238.6 | c.199G>A | p.Val67Met | missense_variant | 1/7 | ENST00000366930.9 | |
TGFB2 | NM_001135599.4 | c.199G>A | p.Val67Met | missense_variant | 1/8 | ||
TGFB2 | NR_138148.2 | n.1565G>A | non_coding_transcript_exon_variant | 1/7 | |||
TGFB2 | NR_138149.2 | n.1565G>A | non_coding_transcript_exon_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB2 | ENST00000366930.9 | c.199G>A | p.Val67Met | missense_variant | 1/7 | 1 | NM_003238.6 | P1 | |
TGFB2 | ENST00000366929.4 | c.199G>A | p.Val67Met | missense_variant | 1/8 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000103 AC: 26AN: 251318Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135884
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GnomAD4 exome AF: 0.000283 AC: 413AN: 1461880Hom.: 1 Cov.: 31 AF XY: 0.000271 AC XY: 197AN XY: 727240
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GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74370
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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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 21, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2021 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 09, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | 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 TGFb propeptide. There is a small physicochemical difference between valine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (30/129,078 alleles) in the European (non-Finnish) population. This variant has been reported in at least two probands/families with aortic aneurysms (PMID: 28139901, 29543232). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 19, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2023 | Identified in an individual with aneurysm of the descending thoracoabdominal aorta (Weerakkody et al., 2018) and in an individual with multiple-aneurysms and/or pseudoaneurysm syndromes (MaPS) (D'Souza et al., 2017); In silico analysis supports 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
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 23, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 28, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at