rs727503471
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_004612.4(TGFBR1):c.799A>G(p.Asn267Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TGFBR1
NM_004612.4 missense
NM_004612.4 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 9.27
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_004612.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TGFBR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.842
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR1 | NM_004612.4 | c.799A>G | p.Asn267Asp | missense_variant | 4/9 | ENST00000374994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR1 | ENST00000374994.9 | c.799A>G | p.Asn267Asp | missense_variant | 4/9 | 1 | NM_004612.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 01, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The Asn267Asp v ariant in TGFBR1 has not been previously reported in any other families with Loe ys-Dietz syndrome or TAAD, but was found to segregate with disease in one affect ed relative in this individual's family (LMM unpublished data). A variant result ing in a different amino acid change at the same position (Asn267His) had previo usly been reported in one individual with clinical features of Loeys-Dietz syndr ome and was reported to segregate in two children, who also had similar clinical features (Matyas 2006). Computational prediction tools and conservation analyse s suggest that the Asn267Asp variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, while the available data on the Asn267Asp variant is suspicious for it to be pathogenic, t he clinical significance of this variant is uncertain. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with Loeys–Dietz syndrome (PMID: 24793577). ClinVar contains an entry for this variant (Variation ID: 165387). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 267 of the TGFBR1 protein (p.Asn267Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;T;D;D
Polyphen
D;P;.;.
Vest4
MutPred
Gain of ubiquitination at K268 (P = 0.1008);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at