ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.3948+4G>A

dbSNP: rs774356396
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001053369 SCV000410216 benign Hereditary sensory neuropathy-deafness-dementia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV001053369 SCV001217627 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2019-03-27 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 327890). This variant is present in population databases (rs774356396, ExAC 0.01%). This sequence change falls in intron 34 of the DNMT1 gene. It does not directly change the encoded amino acid sequence of the DNMT1 protein, but it affects a nucleotide within the consensus splice site of the intron.

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