chr20-32807860-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate
The NM_006892.4(DNMT3B):c.2519G>A(p.Arg840Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,098 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 Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
DNMT3B
NM_006892.4 missense
NM_006892.4 missense
Scores
7
11
1
Clinical Significance
Conservation
PhyloP100: 6.88
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_pathogenic. Variant got 9 ACMG points.
PM1
?
In a helix (size 7) in uniprot entity DNM3B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006892.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DNMT3B
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.854
PP5
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Variant 20-32807860-G-A is Pathogenic according to our data. Variant chr20-32807860-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6744.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-32807860-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT3B | NM_006892.4 | c.2519G>A | p.Arg840Gln | missense_variant | 23/23 | ENST00000328111.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT3B | ENST00000328111.6 | c.2519G>A | p.Arg840Gln | missense_variant | 23/23 | 1 | NM_006892.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251438Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727248
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2002 | - - |
Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2022 | 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. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 16543361, 21549127). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNMT3B protein function. ClinVar contains an entry for this variant (Variation ID: 6744). This variant is also known as R832Q. This missense change has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 12239717). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121908946, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 840 of the DNMT3B protein (p.Arg840Gln). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;T;T;T;D
Sift4G
Uncertain
T;T;T;T;T;T
Polyphen
D;D;P;.;.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0259);.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at