rs587782979
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003242.6(TGFBR2):c.1382G>A(p.Cys461Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TGFBR2
NM_003242.6 missense
NM_003242.6 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a region_of_interest Sufficient for interaction with CLU (size 128) in uniprot entity TGFR2_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in NM_003242.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.954
PP5
Variant 3-30674232-G-A is Pathogenic according to our data. Variant chr3-30674232-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 155839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1382G>A | p.Cys461Tyr | missense_variant | Exon 5 of 7 | 1 | NM_003242.6 | ENSP00000295754.5 | ||
TGFBR2 | ENST00000359013.4 | c.1457G>A | p.Cys486Tyr | missense_variant | Exon 6 of 8 | 1 | ENSP00000351905.4 | |||
TGFBR2 | ENST00000672866.1 | n.2978G>A | non_coding_transcript_exon_variant | Exon 5 of 7 | ||||||
TGFBR2 | ENST00000673203.1 | n.260G>A | non_coding_transcript_exon_variant | Exon 1 of 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 exome
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1
AN:
1461838
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31
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1
AN XY:
727228
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2021 | The c.1382G>A (p.C461Y) alteration is located in exon 5 (coding exon 5) of the TGFBR2 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the cysteine (C) at amino acid position 461 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD), the TGFBR2 c.1382G>A alteration was not observed, with coverage at this position. This alteration has been previously reported in individuals with Loeys-Dietz syndrome type I (Loeys, 2006). Using alternate nomenclature, this variant (p.C486Y, c.1457G>A) has also been reported de novo in a patient with an atrial septal defect (Jin, 2017). Another alteration affecting the same amino acid, p.C461R, was reported in a neonatal female patient with features consistent with Loeys-Dietz syndrome (Valenzuela, 2017). The p.C461 amino acid is conserved in available vertebrate species. The p.C461Y alteration is located in the kinase domain of TGFBR2. Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Tebben, 2016; Zimmermann, 2017). Functional analysis in fibroblasts explanted from a patient with the p.C461Y alteration showed disruption of fibroblast transformation into myofibroblasts with TGF-B1 stimulation; however, the clinical relevance of those results is unclear (Inamoto, 2010). The in silico prediction for the p.C461Y alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Loeys-Dietz syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 26, 2013 | - - |
Loeys-Dietz syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000155839 / PMID: 16928994). A different missense change at the same codon (p.Cys461Arg) has been reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000393299 / PMID: 28344185). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at T458 (P = 0.1562);.;
MVP
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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