chr14-75980923-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_003239.5(TGFB3):​c.-30G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,605,020 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.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TGFB3
NM_003239.5 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: -0.0530

Publications

2 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: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000395 (6/152056) while in subpopulation AFR AF = 0.0000966 (4/41400). AF 95% confidence interval is 0.0000325. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFB3NM_003239.5 linkc.-30G>A 5_prime_UTR_variant Exon 1 of 7 ENST00000238682.8 NP_003230.1 P10600-1A5YM40B3KVH9
TGFB3NM_001329939.2 linkc.-30G>A 5_prime_UTR_variant Exon 2 of 8 NP_001316868.1 P10600-1A5YM40
TGFB3NM_001329938.2 linkc.-30G>A 5_prime_UTR_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.-30G>A 5_prime_UTR_variant Exon 1 of 7 1 NM_003239.5 ENSP00000238682.3 P10600-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000402
AC:
10
AN:
249028
AF XY:
0.0000592
show subpopulations
Gnomad AFR exome
AF:
0.0000641
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000531
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000399
AC:
58
AN:
1452964
Hom.:
0
Cov.:
28
AF XY:
0.0000512
AC XY:
37
AN XY:
723314
show subpopulations
African (AFR)
AF:
0.0000600
AC:
2
AN:
33310
American (AMR)
AF:
0.0000447
AC:
2
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26062
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39658
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86080
European-Finnish (FIN)
AF:
0.0000190
AC:
1
AN:
52534
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5614
European-Non Finnish (NFE)
AF:
0.0000462
AC:
51
AN:
1104900
Other (OTH)
AF:
0.00
AC:
0
AN:
60094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
3
6
8
11
14
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
AF:
0.0000395
AC:
6
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74254
show subpopulations
African (AFR)
AF:
0.0000966
AC:
4
AN:
41400
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4800
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10580
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000815
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Dec 05, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 12529708, 34426522, 31402444, 15639475) -

Sep 17, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The TGFB3 c.-30G>A variant (rs770828281, ClinVar Variation ID: 12474), also known as c.-36G>A, is reported in the literature in multiple individuals in a family affected with arrhythmogenic right ventricular cardiomyopathy (Beffagna 2005). This variant is found in the general population with an overall allele frequency of 0.004% (10/249,028 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the 5' untranslated region and does not create a novel protein translation start codon. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Beffagna G et al. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005 Feb 1;65(2):366-73. PMID: 15639475. -

Arrhythmogenic right ventricular dysplasia 1 Pathogenic:1
Feb 01, 2005
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Uncertain:1
Sep 06, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

TGFB3-related disorder Uncertain:1
May 29, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The TGFB3 c.-30G>A variant is located in the 5' untranslated region. This variant has been reported to segregate with disease in a large family with arrhythmogenic right ventricular dysplasia (Rampazzo et al. 2003. PubMed ID: 12529708; Beffagna et al. 2005. PubMed ID: 15639475). In vitro experimental studies suggest this variant impacts protein function (Beffagna et al. 2005. PubMed ID: 15639475). This variant is reported in 0.0064% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Rienhoff syndrome Uncertain:1
Aug 12, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant occurs in a non-coding region of the TGFB3 gene. It does not change the encoded amino acid sequence of the TGFB3 protein. This variant is present in population databases (rs770828281, ExAC 0.02%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 15639475). This variant is also known as -36G>A. ClinVar contains an entry for this variant (Variation ID: 12474). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TGFB3 function (PMID: 15639475). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.71
CADD
Benign
11
DANN
Benign
0.82
PhyloP100
-0.053
PromoterAI
-0.041
Neutral
Mutation Taster
=70/230
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs770828281; hg19: chr14-76447266; API