rs771543236
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_003239.5(TGFB3):āc.77C>Gā(p.Thr26Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
TGFB3
NM_003239.5 missense
NM_003239.5 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 8.03
Genes affected
TGFB3 (HGNC:11769): (transforming growth factor beta 3) 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. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]
IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.4023807).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.77C>G | p.Thr26Ser | missense_variant | 1/7 | ENST00000238682.8 | |
TGFB3 | NM_001329939.2 | c.77C>G | p.Thr26Ser | missense_variant | 2/8 | ||
TGFB3 | NM_001329938.2 | c.77C>G | p.Thr26Ser | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.77C>G | p.Thr26Ser | missense_variant | 1/7 | 1 | NM_003239.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2017 | The T26S variant in the TGFB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T26S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T26S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T26S as a variant of uncertain significance, which may be related to the reported arrhythmia in this individual. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2016 | - - |
Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
Rienhoff syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 26 of the TGFB3 protein (p.Thr26Ser). This variant is present in population databases (rs771543236, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of TGFB3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 392089). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP
MPC
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