rs77355896
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_006892.4(DNMT3B):c.1996+6C>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,152 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
DNMT3B
NM_006892.4 splice_donor_region, intron
NM_006892.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00009154
2
Clinical Significance
Conservation
PhyloP100: -0.0280
Genes affected
DNMT3B (HGNC:2979): (DNA methyltransferase 3 beta) CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined. [provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT3B | NM_006892.4 | c.1996+6C>G | splice_donor_region_variant, intron_variant | ENST00000328111.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT3B | ENST00000328111.6 | c.1996+6C>G | splice_donor_region_variant, intron_variant | 1 | NM_006892.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152222Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461812Hom.: 0 Cov.: 35 AF XY: 0.0000440 AC XY: 32AN XY: 727216
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152340Hom.: 1 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74506
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2022 | This sequence change falls in intron 18 of the DNMT3B gene. It does not directly change the encoded amino acid sequence of the DNMT3B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs77355896, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DNMT3B-related conditions. Variants that disrupt 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at