rs896156575

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003238.6(TGFB2):​c.445T>G​(p.Phe149Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TGFB2
NM_003238.6 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TGFB2NM_003238.6 linkuse as main transcriptc.445T>G p.Phe149Val missense_variant 2/7 ENST00000366930.9 NP_003229.1
TGFB2NM_001135599.4 linkuse as main transcriptc.529T>G p.Phe177Val missense_variant 3/8 NP_001129071.1
TGFB2NR_138148.2 linkuse as main transcriptn.1811T>G non_coding_transcript_exon_variant 2/7
TGFB2NR_138149.2 linkuse as main transcriptn.1895T>G non_coding_transcript_exon_variant 3/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TGFB2ENST00000366930.9 linkuse as main transcriptc.445T>G p.Phe149Val missense_variant 2/71 NM_003238.6 ENSP00000355897 P1P61812-1
TGFB2ENST00000366929.4 linkuse as main transcriptc.529T>G p.Phe177Val missense_variant 3/81 ENSP00000355896 P61812-2
TGFB2ENST00000488793.1 linkuse as main transcriptn.109T>G non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 20, 2022In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 459267). This variant has not been reported in the literature in individuals affected with TGFB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 149 of the TGFB2 protein (p.Phe149Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.61
D;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D;T
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.2
N;D
REVEL
Uncertain
0.33
Sift
Benign
0.058
T;T
Sift4G
Uncertain
0.032
D;D
Polyphen
0.55
P;D
Vest4
0.76
MutPred
0.59
Gain of MoRF binding (P = 0.0955);.;
MVP
0.51
MPC
1.7
ClinPred
0.90
D
GERP RS
5.1
Varity_R
0.25
gMVP
0.55

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.

Other links and lift over

dbSNP: rs896156575; hg19: chr1-218578609; API