NM_022552.5:c.901C>T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BS2_Supporting
The NM_022552.5(DNMT3A):c.901C>T(p.Arg301Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_022552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461332Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726992
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29900417) -
Inborn genetic diseases Uncertain:1
The c.901C>T (p.R301W) alteration is located in exon 8 (coding exon 7) of the DNMT3A gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to be de novo in an individual with postnatal overgrowth (height and head circumference greater than two standard deviations above the mean), mild intellectual disability, and joint hypermobility (Tatton-Brown, 2018). Additionally, this alteration was reported in an individual with overgrowth, developmental delay, and autism (Smith, 2021). This amino acid position is well conserved in available vertebrate species. The p.R301 amino acid is located in the PWWP domain of the DNMT3A protein, which spans 143 amino acid residues (Qiu, 2002). The PWWP domain is named after a highly conserved proline-tryptophan-tryptophan-proline motif, but in DNMT3A and DNMT3B, this motif consists of serine-tryptophan-tryptophan-proline (amino acid residues 304-307). Disruption of the PWWP domains in DNMT3A and DNMT3B prevents the association with heterochromatin and abolishes their methylation ability, suggesting that the PWWP domain plays an important role in the functional specialization of DNMT3A (Chen, 2004). The in silico prediction for this alteration is inconclusive. 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