ClinVar Miner

Submissions for variant NM_006892.4(DNMT3B):c.2421-11G>A

gnomAD frequency: 0.00001  dbSNP: rs547940069
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268751 SCV001447909 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneDx RCV001268751 SCV003933495 likely pathogenic not provided 2022-12-14 criteria provided, single submitter clinical testing Reported with another DNMT3B variant in at least two unrelated individuals with ICF syndrome, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Okano et al.,1999, Hansen et al., 1999; Jiang et al., 2005); Published functional studies suggest this variant results in aberrant splicing (Okano et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 28334849, 22378288, 10555141, 27153398, 17893117, 28916186, 21147113, 9718351, 3361388, Shirkani_2020, 23486536, 17908720, 15580563, 10588719, 11102980)
Labcorp Genetics (formerly Invitae), Labcorp RCV003593854 SCV004298052 likely pathogenic Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency 2023-03-27 criteria provided, single submitter clinical testing Studies have shown that this variant results in the activation of a cryptic splice site in intron 21 (PMID: 10588719). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6741). This variant is also known as IVS21-11G>A, c.2397-11G>A, and STP (SerThrPro) ins807. This variant has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome and/or syndromic combined immunodeficiency (PMID: 10588719, 17908720, 28916186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 sequence change falls in intron 22 of the DNMT3B gene. It does not directly change the encoded amino acid sequence of the DNMT3B protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007133 SCV005887500 pathogenic Immunodeficiency-centromeric instability-facial anomalies syndrome 1 2025-01-24 criteria provided, single submitter clinical testing Variant summary: DNMT3B c.2421-11G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and creates an alternate 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, creating a new splice acceptor site that adds nine nucleotides to the 3' end of exon 22, effectively creating an insertion of SerThrPro just before Arg 807 (e.g. Hansen_1999). The variant allele was found at a frequency of 4e-06 in 250058 control chromosomes. c.2421-11G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with ICF Syndrome (e.g. Hansen_1999, Hagleitner_2007, Abolhassani_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28916186, 17893117, 10588719). ClinVar contains an entry for this variant (Variation ID: 6741). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000007133 SCV000027329 pathogenic Immunodeficiency-centromeric instability-facial anomalies syndrome 1 1999-10-29 no assertion criteria provided literature only

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