rs387906696
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2
The NM_004612.4(TGFBR1):āc.134A>Gā(p.Asn45Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,613,766 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 Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. N45N) has been classified as Likely benign.
Frequency
Consequence
NM_004612.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR1 | NM_004612.4 | c.134A>G | p.Asn45Ser | missense_variant | 2/9 | ENST00000374994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR1 | ENST00000374994.9 | c.134A>G | p.Asn45Ser | missense_variant | 2/9 | 1 | NM_004612.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251002Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135644
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461664Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727136
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74286
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 13, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 29915). This missense change has been observed in individuals with multiple self-healing squamous epithelioma and/or thoracic aortic aneurysms and dissections (PMID: 21358634, 29907982, 33824467; Invitae). This variant is present in population databases (rs387906696, gnomAD 0.004%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 45 of the TGFBR1 protein (p.Asn45Ser). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in a Scottish family with Multiple self-healing squamous epithelioma (MSSE - 2 affected and 1 unaffected relative). This variant is classified in ClinVar with 1 star as Pathogenic by GeneDx and a risk factor by OMIM. It has a Max MAF of 0.006% in ExAC (1 allele) and 0.003% in gnomAD (1 allele). - |
Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
Loeys-Dietz syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 17, 2023 | This missense variant replaces asparagine with serine at codon 45 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and dissection, one sporadic and the other with family history of thoracic aortic aneurysm and dissection and sudden unexplained death (PMID: 29907982, 33824467). This variant has also been reported in two related individuals affected with multiple self-healing squamous epithelioma as well as in an unaffected family member (PMID: 21358634). This variant has been identified in 3/282384 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Isolated thoracic aortic aneurysm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Identified in an individual with aortic dissection, multiple aortic and arterial aneurysms, hypermobility, and a significant family history, although segregation data was not available (Overwater et al., 2018); Observed in one Scottish family with multiple self-healing squamous epithelioma (MSSE); however, it was identified in two symptomatic relatives and one asymptomatic relative (Goudie D et al., 2011), and additional evidence is needed to establish the association between TGFBR1 variants and MSSE; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25275298, 23358093, 28498993, 23358096, 24747516, 33824467, 29907982, 21358634) - |
Multiple self-healing squamous epithelioma Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Feb 27, 2011 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at