chr2-25234307-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PP3_ModeratePP5_Very_StrongBS2_Supporting
The NM_022552.5(DNMT3A):c.2711C>T(p.Pro904Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,504 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
Consequence
NM_022552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152098Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251116Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135708
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461406Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727020
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152098Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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The P904L variant in the DNMT3A gene has been reported previously as a de novo variant in a patient with overgrowth and moderate intellectual disability (Tatton-Brown et al., 2014). The P904L variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P904L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position within the C-terminal DNA methyltransferase domain (Tatton-Brown et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. The P904L variant is a strong candidate for a pathogenic variant. -
Tatton-Brown-Rahman overgrowth syndrome Pathogenic:1
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EBV-positive nodal T- and NK-cell lymphoma Pathogenic:1
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Autism spectrum disorder;C4014545:Tatton-Brown-Rahman overgrowth syndrome Other:1
Variant reported in multiple GenomeConnect participants by GeneDx. Variant classified most recently as Pathogenic on 11-13-2021 and as Likely pathogenic on 05-02-2016. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne?from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at