3-30606547-T-A
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001407129.1(TGFBR2):c.-58T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 284,278 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (★★).
Frequency
Genomes: 𝑓 0.000053 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
TGFBR2
NM_001407129.1 5_prime_UTR_premature_start_codon_gain
NM_001407129.1 5_prime_UTR_premature_start_codon_gain
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.21
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 Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TGFBR2 | NM_001407129.1 | c.-58T>A | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 8 | NP_001394058.1 | |||
TGFBR2 | NM_001407132.1 | c.-58T>A | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 7 | NP_001394061.1 | |||
LOC105377015 | XM_047449400.1 | c.378A>T | p.Gln126His | missense_variant | Exon 1 of 2 | XP_047305356.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152148Hom.: 1 Cov.: 32
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GnomAD4 exome AF: 0.0000227 AC: 3AN: 132130Hom.: 0 Cov.: 0 AF XY: 0.0000156 AC XY: 1AN XY: 64064
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152148Hom.: 1 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74334
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ClinVar
Significance: Uncertain significance/Uncertain risk allele
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 14, 2021 | This variant occurs in a non-coding region of the TGFBR2 gene. It does not change the encoded amino acid sequence of the TGFBR2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 16799921). 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 have shown that this variant affects TGFBR2 protein function (PMID: 16799921). 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. - |
Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 04, 2021 | - - |
Diabetic retinopathy Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs1038796042 with diabetic retinopathy. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at