rs148665451
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_003242.6(TGFBR2):c.985G>A(p.Ala329Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A329V) has been classified as Uncertain significance.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.985G>A | p.Ala329Thr | missense_variant | 4/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.985G>A | p.Ala329Thr | missense_variant | 4/7 | 1 | NM_003242.6 | P1 | |
TGFBR2 | ENST00000359013.4 | c.1060G>A | p.Ala354Thr | missense_variant | 5/8 | 1 | |||
TGFBR2 | ENST00000672866.1 | n.2581G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 26AN: 250970Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135654
GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461800Hom.: 0 Cov.: 34 AF XY: 0.0000798 AC XY: 58AN XY: 727194
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74344
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2020 | This variant is associated with the following publications: (PMID: 21267002, 16928994, 24055113, 25637381, 23884466, 17061023, 30739908, 32152251) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 10, 2021 | The TGFBR2 c.985G>A; p.Ala329Thr variant (rs149425237) has been identified in multiple individuals included in cohorts of Loeys-Dietz syndrome patients or thoracic aortic aneurysms and dissections (TAAD; Barnett 2011, Frischmeyer-Guerrerio 2013, Jani 2020, Loeys 2006). However, this variant is found in the general population with an allele frequency in Ashkenazi Jewish individuals of 0.19% (20/10,346 alleles) in the Genome Aggregation Database. The alanine at codon 329 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.59). Based on the available information, the clinical significance of this variant is uncertain. References: Barnett et al. Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? Eur J Hum Genet. 2011 Jun;19(6):624-33. PMID: 21267002 Frischmeyer-Guerrerio et al. TGFß receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med. 2013 Jul 24;5(195):195ra94. PMID: 23884466 Jani et al. Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation. J Med Genet. 2020 Oct;57(10):699-707. PMID: 32152251 Loeys et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. PMID: 16928994 - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | TGFBR2: BS2 - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 08, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Loeys-Dietz syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Marfan syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
TGFBR2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 22, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at