3-30672302-G-A
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_003242.6(TGFBR2):c.1119G>A(p.Met373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,608,076 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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TGFBR2 | ENST00000295754.10 | c.1119G>A | p.Met373Ile | missense_variant | Exon 4 of 7 | 1 | NM_003242.6 | ENSP00000295754.5 | ||
TGFBR2 | ENST00000359013.4 | c.1194G>A | p.Met398Ile | missense_variant | Exon 5 of 8 | 1 | ENSP00000351905.4 | |||
TGFBR2 | ENST00000672866.1 | n.2715G>A | non_coding_transcript_exon_variant | Exon 4 of 7 |
Frequencies
GnomAD3 genomes AF: 0.00131 AC: 200AN: 152202Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00144 AC: 354AN: 246454Hom.: 2 AF XY: 0.00134 AC XY: 178AN XY: 132926
GnomAD4 exome AF: 0.00175 AC: 2544AN: 1455756Hom.: 9 Cov.: 34 AF XY: 0.00171 AC XY: 1237AN XY: 723518
GnomAD4 genome AF: 0.00131 AC: 199AN: 152320Hom.: 1 Cov.: 33 AF XY: 0.00134 AC XY: 100AN XY: 74474
ClinVar
Submissions by phenotype
not provided Benign:7
TGFBR2: BS1 -
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This variant is associated with the following publications: (PMID: 17344846, 16928994, 9395234, 23884466, 27153395, 18781618) -
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Familial thoracic aortic aneurysm and aortic dissection Benign:6
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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. -
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not specified Benign:5
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LB/B > 4 on ClinVar or LB/B > 2 Rep -
This variant has previously been reported in the literature in an individual wit h clinical features of Loeys-Dietz syndrome; however, the variant was also found in 1/200 control chromosomes (Loeys 2006) and in the reportedly unaffected pare nt of a proband in our laboratory. In addition, this residue is not highly conse rved through different species, which raises the possibility that amino acid cha nges at this position may be tolerated. Therefore, this variant is likely to be benign. -
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Loeys-Dietz syndrome Uncertain:1Benign:2
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Marfan syndrome Benign:2
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Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Benign:1
TGFBR2 NM_003242.5 exon 4 p.Met373Ile (c.1119G>A): This variant has been reported in the literature in one individual with Loeys-Dietz syndrome (Frischmeyer-Guerrerio 2013 PMID:23884466). However, this variant isalso present in 0.3% (47/13666) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-30672302-G-A?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:36859). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -
Ehlers-Danlos syndrome Benign:1
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Loeys-Dietz syndrome 2 Benign:1
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Connective tissue disorder Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at