ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.99G>A (p.Ser33=) (rs147710692)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479881 SCV000574229 uncertain significance not provided 2017-03-22 criteria provided, single submitter clinical testing The c.99 G>A variant of uncertain significance in the TMEM43 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although c.99 G>A results in a synonymous amino acid substitution (S33S), in silico splice prediction programs predict this variant may create a cryptic splice donor site upstream from the natural splice donor site, and may cause abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Furthermore, this substitution occurs at a nucleotide that is not conserved across species, and adenine (A) is the wild-type nucleotide at this position in some species. Finally, no pathogenic splice site variants in the TMEM43 gene have been reported in the Human Gene Mutation Database (Stenson et al., 2014).
Integrated Genetics/Laboratory Corporation of America RCV000780775 SCV000918315 likely benign not specified 2017-12-21 criteria provided, single submitter clinical testing Variant summary: The TMEM43 c.99G>A (p.Ser33Ser) variant involves the alteration of a not conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict this variant may impact normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/246134 control chromosomes in gnomAD at a frequency of 0.0000122, which is slightly above the estimated maximal expected allele frequency of a pathogenic TMEM43 variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant was identified in an internal specimen together with a known pathogenic variant in the KCNQ1 gene. However, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.

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