DNMT3A c.1903C>T, p.Arg635Trp
NM_022552.4:c.1903C>T
COSMIC ID: COSM1407108
Likely Pathogenic
DNMT3A p.R635W meets one strong functional criterion (PS3), one moderate rarity criterion (PM2), and two supporting criteria (PP3 computational, PP5 ClinVar reports), which collectively supports a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM2
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
DNMT3A
Transcript
NM_022552.5
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_022552.4 | RefSeq Select | 23 exons | Reverse |
| NM_022552.3 | Alternative | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_022552.4:c.1903C>T
Protein Change
R635W
Location
Exon 16
(Exon 16 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 635 in gene DNMT3A
Alternate Identifiers
COSM1407108
Variant interpretation based on transcript NM_022552.5
Genome Browser
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HGVS InputNM_022552:c.1903C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00635%
Rare
Highest in Population
African/African American
0.0225%
Low Frequency
Global: 0.00635%
African/African American: 0.0225%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 157464Alt: 10Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00635%, 10/157464 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0225%, 2/8878 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Likely Pathogenic
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
2 Path
4 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 635 of the DNMT3A protein (p.Arg635Trp). This variant is present in population databases (rs144689354, gnomAD 0.01%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 23849776, 27525107, 31981491). ClinVar contains an entry for this variant (Variation ID: 284904). 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 DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 31861499). This variant disrupts the p.Arg635 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32435502; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
The c.1903C>T (p.R635W) alteration is located in exon 16 (coding exon 15) of the DNMT3A gene. This alteration results from a C to T substitution at nucleotide position 1903, causing the arginine (R) at amino acid position 635 to be replaced by a tryptophan (W). for Tatton-Brown-Rahman syndrome; however, its clinical significance for Heyn-Sproul-Jackson syndrome is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (10/157464) total alleles studied. The highest observed frequency was 0.023% (2/8878) of African alleles. Of note, somatic mosaicism in individuals in general population databases cannot be ruled out as this gene shows evidence of clonal hematopoiesis of indeterminate potential (CHIP). This variant was reported in individual(s) with features consistent with Tatton-Brown-Rahman syndrome; in at least one individual, it was determined to be de novo (DECIPHER; NCBI ClinVar). Another variant at the same codon, c.1904G>A (p.R635Q), has been identified in individual(s) with features consistent with Tatton-Brown-Rahman syndrome (Yokoi, 2020; Cecchi, 2022). Manual reference: National Center for Biotechnology Information. ClinVar; [VCV000284904.15], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000284904.15 (accessed Jan. 23, 2025). This amino acid position is highly conserved in available vertebrate species. In an assay testing DNMT3A function, this variant showed functionally abnormal results (Khrabrova, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (4 clinical laboratories).
COSMIC ID
COSM1407108
Recurrence
27 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 635 in gene DNMT3A
Functional Summary
The DNMT3A R635W variant has been functionally characterized and demonstrates a damaging effect. In vitro studies show that this mutation results in loss of methyltransferase function, reduced protein stability, failure to bind DNA, and decreased activation by Dnmt3L. These findings indicate a loss of function in the DNMT3A protein, supporting its likely oncogenic role in hematologic malignancies.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.844
0.844
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 6.16
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (R635W), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant requirement.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no report of another nucleotide change causing the same R635W substitution. Therefore, this criterion is not applied due to lack of evidence of a different nucleotide change producing R635W.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: in vitro studies demonstrate loss of methyltransferase function, reduced protein stability, failure to bind DNA, and decreased activation by Dnmt3L for DNMT3A R635W. Therefore, this criterion is applied at Strong strength because the functional data clearly support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data quantifying increased prevalence in affected individuals. Therefore, this criterion is not applied due to lack of comparative prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no specific data indicating R635 resides in a recognized mutational hotspot or functional domain lacking benign variation. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: present in gnomAD at MAF=0.00635% (10/157,464 alleles) with no homozygotes, which is below the threshold for rare variants. Therefore, this criterion is applied at Moderate strength because the variant is at an extremely low frequency in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: gene is associated with dominant hematologic malignancy predisposition and no data on trans configuration with another variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no report of any other missense change at residue R635 classified as pathogenic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no information on presumed de novo status. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: DNMT3A has both loss-of-function and missense mechanisms in malignancy, but no specific gene-level constraint data provided. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: REVEL score of 0.84 (exceeds 0.75 threshold), PolyPhen, MetaSVM, MetaLR, and PrimateAI all predict damaging effects, with minimal splicing impact. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar entries include 2 Pathogenic and 4 Likely Pathogenic classifications from reputable clinical laboratories, without full evidence available. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0.00635% which is well below any threshold for common benign variants. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: frequency is extremely low and not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no information on health status of carriers in population databases. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate damaging effect, not benign. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: DNMT3A disease mechanism includes functional disruption by missense in malignancy. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on phase with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational predictions support deleterious impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no data on alternate molecular diagnoses. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no reputable source reports this variant as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied.