14-75980806-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003239.5(TGFB3):​c.88T>A​(p.Leu30Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L30L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TGFB3
NM_003239.5 missense

Scores

10
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.630

Publications

0 publications found
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]
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]
IFT43 Gene-Disease associations (from GenCC):
  • cranioectodermal dysplasia 3
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • short-rib thoracic dysplasia 18 with polydactyly
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • cranioectodermal dysplasia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • ciliopathy
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
  • retinitis pigmentosa 81
    Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32967037).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFB3NM_003239.5 linkc.88T>A p.Leu30Met missense_variant Exon 1 of 7 ENST00000238682.8 NP_003230.1 P10600-1A5YM40B3KVH9
TGFB3NM_001329939.2 linkc.88T>A p.Leu30Met missense_variant Exon 2 of 8 NP_001316868.1 P10600-1A5YM40
TGFB3NM_001329938.2 linkc.88T>A p.Leu30Met missense_variant Exon 1 of 5 NP_001316867.1 P10600-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFB3ENST00000238682.8 linkc.88T>A p.Leu30Met missense_variant Exon 1 of 7 1 NM_003239.5 ENSP00000238682.3 P10600-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.80
T;T
M_CAP
Benign
0.070
D
MetaRNN
Benign
0.33
T;T
MetaSVM
Uncertain
-0.046
T
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
0.63
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.33
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.99
D;.
Vest4
0.14
MutPred
0.66
Gain of catalytic residue at L30 (P = 0.0363);Gain of catalytic residue at L30 (P = 0.0363);
MVP
0.52
MPC
1.4
ClinPred
0.87
D
GERP RS
4.6
PromoterAI
0.041
Neutral
Varity_R
0.35
gMVP
0.36
Mutation Taster
=88/12
polymorphism

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

Other links and lift over

dbSNP: rs3917145; hg19: chr14-76447149; API