9-99105218-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004612.4(TGFBR1):​c.13G>A​(p.Val5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TGFBR1
NM_004612.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.38

Publications

0 publications found
Variant links:
Genes affected
TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
TGFBR1 Gene-Disease associations (from GenCC):
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • Loeys-Dietz syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • Loeys-Dietz syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
  • multiple self-healing squamous epithelioma
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10283682).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFBR1NM_004612.4 linkc.13G>A p.Val5Ile missense_variant Exon 1 of 9 ENST00000374994.9 NP_004603.1 P36897-1Q5T7S2B4DXN7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFBR1ENST00000374994.9 linkc.13G>A p.Val5Ile missense_variant Exon 1 of 9 1 NM_004612.4 ENSP00000364133.4 P36897-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
933154
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
438288
African (AFR)
AF:
0.00
AC:
0
AN:
18364
American (AMR)
AF:
0.00
AC:
0
AN:
3620
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
8674
East Asian (EAS)
AF:
0.00
AC:
0
AN:
12484
South Asian (SAS)
AF:
0.00
AC:
0
AN:
18272
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
7966
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2148
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
828042
Other (OTH)
AF:
0.00
AC:
0
AN:
33584
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Nov 12, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5 of the TGFBR1 protein (p.Val5Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. 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 TGFBR1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
T;.;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.079
N
LIST_S2
Benign
0.60
T;T;T
M_CAP
Pathogenic
0.71
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.0
N;N;N
PhyloP100
-1.4
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.34
N;N;N
REVEL
Benign
0.16
Sift
Benign
0.47
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.0050
B;B;.
Vest4
0.13
MutPred
0.22
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
0.40
MPC
0.41
ClinPred
0.045
T
GERP RS
1.7
PromoterAI
0.067
Neutral
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.1
Varity_R
0.046
gMVP
0.25
Mutation Taster
=95/5
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: rs2118163054; hg19: chr9-101867500; API