20-32807793-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong
The NM_006892.4(DNMT3B):c.2452G>A(p.Val818Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_006892.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251326Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135854
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727232
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Pathogenic:3
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The DNMT3B c.2452G>A (p.Val818Met) variant, also referred to as p.Val810Met, has been reported in three studies and is found in four individuals, two with the variant in a homozygous state and two with the variant in a compound heterozygous. All individuals were diagnosed with immunodeficiency-centromeric instability-facial anomalies syndrome (Xu et al. 1999; Wijmenga et al. 2000; Jiang et al. 2005). The parents of one homozygous individual were confirmed to be unaffected heterozygous carriers (Xu et al. 1999). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Val818Met variant is present in a catalytic domain. Gowher and Jeltsch (2002) used site directed mutagenesis of murine cDNA to generate variant protein which was evaluated to quantify the effect on catalytic activity. The rate of DNA methylation of classical satellites was found to be <10% of wild type. A second study that used patient leukocyte or fibroblast cultures also noted hypomethylation of the classical satellites, whereas the alpha satellites had methylation comparable to wild type (Jiang et al. 2005). Based on the collective evidence, the p.Val818Met variant is classified as pathogenic for immunodeficiency-centromeric instability-facial anomalies syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Variant summary: DNMT3B c.2452G>A (p.Val818Met) results in a conservative amino acid change located in the S-adenosyl-L-methionine-dependent methyltransferases (IPR029063) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251326 control chromosomes. c.2452G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with ICF Syndrome, Type 1 (Xu_1999, Wijmenga_2000, Jiang_2005). These data indicate that the variant is likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal methylation activity (Gowher_2002, Cho_2024). The following publications have been ascertained in the context of this evaluation (PMID: 39290110, 11919202, 15580563, 11102980, 10647011). ClinVar contains an entry for this variant (Variation ID: 6734). Based on the evidence outlined above, the variant was classified as pathogenic. -
Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 818 of the DNMT3B protein (p.Val818Met). This variant is present in population databases (rs121908940, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome (PMID: 10647011, 11102980, 15580563). This variant is also known as p.V810M. ClinVar contains an entry for this variant (Variation ID: 6734). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DNMT3B protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 11919202). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at