ClinVar Miner

Submissions for variant NM_001142301.1(TMEM67):c.1431+5A>T (rs863224813)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196421 SCV000255216 uncertain significance Joubert syndrome; Meckel-Gruber syndrome 2015-09-02 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the TMEM67 mRNA. It does not directly change the encoded amino acid sequence of the TMEM67 protein. This sequence change affects a highly conserved nucleotide within the consensus donor splice site of intron 16. The majority of introns (75-85%) have a G at this position (PMID: 9536098). This variant has not been published in the literature and is not present in population databases. Nucleotide substitutions at the +5 position of the intron are relatively common causes of aberrant splicing (PMID: 17576681) but according to multiple splice algorithms (NNSPLICE, SpliceSiteFinder-like, MaxEntScan, GeneSplicer, Human Splicing Finder ) this particular c.1674+5 A>T variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published transcriptional studies. In summary, this is a novel intronic change that is not predicted to affect mRNA splicing or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.

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