chr20-32805387-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The ENST00000328111.6(DNMT3B):āc.2281G>Cā(p.Glu761Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000328111.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNMT3B | NM_006892.4 | c.2281G>C | p.Glu761Gln | missense_variant | 21/23 | ENST00000328111.6 | NP_008823.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNMT3B | ENST00000328111.6 | c.2281G>C | p.Glu761Gln | missense_variant | 21/23 | 1 | NM_006892.4 | ENSP00000328547 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152100Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251468Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727236
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74298
ClinVar
Submissions by phenotype
Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 761 of the DNMT3B protein (p.Glu761Gln). This variant is present in population databases (rs767814649, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome (PMID: 31686314; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 572547). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT3B protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2021 | The c.2281G>C (p.E761Q) alteration is located in exon 21 (coding exon 20) of the DNMT3B gene. This alteration results from a G to C substitution at nucleotide position 2281, causing the glutamic acid (E) at amino acid position 761 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at