Classification rationale

PM2PP3 VUS

DNMT3A c.2116G>C

The DNMT3A c.2116G>C (p.Gly706Arg; p.G706R) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.² OncoKB classifies this variant as Likely Oncogenic with a likely loss-of-function biological effect, but the available evidence does not provide a well-established variant-specific functional study result sufficient for ACMG PS3 or BS3.³ Computational evidence supports a deleterious protein effect, with REVEL 0.971, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.⁴

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗PMID:34429321 ↗

4 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_022552.4 · variants mapped to exon structure

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 threshold of 0.1% for non-VCEP review and supports rarity in the general population.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

Computational evidence supports a deleterious effect for this missense variant. REVEL is 0.971, which is strongly damaging in silico, while SpliceAI shows no meaningful splice effect with a max delta score of 0.04, supporting a protein-altering rather than splice-altering mechanism.

REVEL score 0.971.SpliceAI max delta score 0.04below typical splice-impact concern thresholds.

spliceai ↗

Assessed · not applied · 9 not met · 12 not assessed

Pathogenic

PS1 No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant.

PS2 No confirmed de novo occurrence with verified parentage was identified.

PS3 Available evidence cites functional literature and OncoKB describes this variant as likely oncogenic with a likely loss-of-function effect, but no well-established functional study result for this specific variant was identified that is sufficient to apply ACMG PS3.

PS4 No enrichment of this variant in affected individuals compared with controls was identified.

PM1 Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation.

PM5 No evidence was identified showing a different pathogenic missense change at codon 706 that would support PM5.

PM6 No assumed de novo occurrence was identified.

PP1 No segregation data were identified for this variant.

PP2 Gene-level missense constraint or a low rate of benign missense variation sufficient for PP2 was not established in the available evidence.

PP4 No phenotype or family history information was provided that is sufficiently specific to DNMT3A-related disease to support PP4.

PP5 No reputable germline database classification supporting pathogenicity was identified because this variant is absent from ClinVar.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign stand-alone threshold of 1%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign strong threshold of 0.3%.

BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2.

BS3 Reviewed evidence does not identify well-established functional studies showing normal protein function for this specific variant.

BS4 No segregation data showing lack of cosegregation were identified.

BP1 The available evidence does not establish that missense variation is generally a non-disease mechanism for DNMT3A, so BP1 was not applied.

BP2 No phase information with another pathogenic variant was identified.

BP4 Available computational evidence does not support a benign effect.

BP5 No alternate molecular explanation for disease was identified.

BP6 No reputable germline database classification supporting benignity was identified because this variant is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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