9-99105255-TGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGC
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_004612.4(TGFBR1):c.70_78dupGCGGCGGCG(p.Ala24_Ala26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,043,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004612.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000632 AC: 9AN: 142424Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.0000610 AC: 55AN: 900970Hom.: 0 Cov.: 7 AF XY: 0.0000615 AC XY: 26AN XY: 422764
GnomAD4 genome AF: 0.0000632 AC: 9AN: 142424Hom.: 0 Cov.: 30 AF XY: 0.0000577 AC XY: 4AN XY: 69286
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
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. -
This variant, c.70_78dup, results in the insertion of 3 amino acid(s) of the TGFBR1 protein (p.Ala24_Ala26dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 408570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 provided Uncertain:1Benign:1
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The TGFBR1 c.70_78dup; p.Ala24_Ala26dup variant (rs11466445), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 408570). This variant is found in the general population with an overall allele frequency of 0.008% (2/23,942 alleles) in the Genome Aggregation Database. This variant is three amino acid, in-frame expansion of the polyalanine track in exon 1 of TGFBR1. In-frame contractions of this track are found at relatively high frequency in the general population and are mostly considered benign (ClinVar; Skoglund 2007). Expansions of this track are less frequent, although a single alanine duplication has been reported in a patient with a Marfan-related disorder (Seo 2018). Based on the available information, the clinical significance of the p.Ala24_Ala26dup variant is uncertain. Seo GH et al. The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. Medicine (Baltimore). 2018 May;97(20):e10767. Skoglund J et al. Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clin Cancer Res. 2007 Jun 15;13(12):3748-52. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at