rs779897294

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003239.5(TGFB3):​c.626G>T​(p.Arg209Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TGFB3
NM_003239.5 missense

Scores

4
12
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.65
Variant links:
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]
TGFB3-AS1 (HGNC:53144): (TGFB3 antisense RNA 1)
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFB3NM_003239.5 linkc.626G>T p.Arg209Leu missense_variant Exon 3 of 7 ENST00000238682.8 NP_003230.1 P10600-1A5YM40B3KVH9
TGFB3NM_001329939.2 linkc.626G>T p.Arg209Leu missense_variant Exon 4 of 8 NP_001316868.1 P10600-1A5YM40
TGFB3NM_001329938.2 linkc.626G>T p.Arg209Leu missense_variant Exon 3 of 5 NP_001316867.1 P10600-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFB3ENST00000238682.8 linkc.626G>T p.Arg209Leu missense_variant Exon 3 of 7 1 NM_003239.5 ENSP00000238682.3 P10600-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251278
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461764
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-0.53
T
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.023
D;T
Sift4G
Benign
0.12
T;D
Polyphen
0.57
P;.
Vest4
0.92
MutPred
0.66
Gain of catalytic residue at R209 (P = 0.0042);Gain of catalytic residue at R209 (P = 0.0042);
MVP
0.92
MPC
1.8
ClinPred
0.97
D
GERP RS
5.5
Varity_R
0.52
gMVP
0.75

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: rs779897294; hg19: chr14-76437489; API