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DNMT3Ac.2116G>CUncertain significance
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Variant interpretation report

DNMT3A c.2116G>C, p.(Gly706Arg)

NM_022552.4:c.2116G>C NP_072046.2:p.(Gly706Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About DNMT3A

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate

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.

PP3Supporting
PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The DNMT3A c.2116G>C (p.Gly706Arg; p.G706R) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.

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.

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.

Met · 2

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingComputational 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.971.
  • SpliceAI max delta score 0.04
  • below typical splice-impact concern thresholds.
Sources
spliceai ↗

Not met · 9 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • OncoKB classifies DNMT3A p.G706R as Likely Oncogenic with likely loss-of-function biological effect.
  • Reviewed literature queue included PMID:27359055 and PMID:34429321
  • but the available case materials did not provide a PS3-qualifying variant-specific assay result.
Still missing
  • No variant-specific validated functional assay result was identified in the reviewed evidence.
Sources
oncokb ↗PMID:27359055 ↗PMID:34429321 ↗
PS4 No enrichment of this variant in affected individuals compared with controls was identified. This variant has not been reported in ClinVar, and no qualifying case-control or case-series evidence was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for NM_022552.4:c.2116G>C.
Still missing
  • No germline case-count or case-control dataset was identified.
Sources
clinvar ↗
PM1 Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, and the reviewed literature did not establish PM1-level domain evidence for this specific variant. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review did not identify a statistically significant hotspot for DNMT3A G706.
  • PMID:27359055 and PMID:34429321 were screened for PM1 relevance but did not provide sufficient PM1 evidence in the available materials.
Still missing
  • No confirmed hotspot or critical-domain evidence meeting PM1 was identified.
Sources
hotspots ↗PMID:27359055 ↗PMID:34429321 ↗
PP5 No reputable germline database classification supporting pathogenicity was identified because this variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign stand-alone threshold of 1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the benign strong threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Reviewed evidence does not identify well-established functional studies showing normal protein function for this specific variant. OncoKB instead describes the variant as likely oncogenic with likely loss-of-function effect, so BS3 is not supported. Details ▾Hide ▴
Evidence considered
  • OncoKB classifies DNMT3A p.G706R as Likely Oncogenic with likely loss-of-function biological effect.
  • PMID:34429321 was screened for BS3 relevance
  • but the available materials did not support normal-function evidence for this variant.
Still missing
  • No variant-specific functional evidence demonstrating normal function was identified.
Sources
oncokb ↗PMID:34429321 ↗PMID:27359055 ↗
BP4 Available computational evidence does not support a benign effect. REVEL is 0.971, which argues against BP4, and SpliceAI predicts no meaningful splice effect with a max delta score of 0.04. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.971.
  • SpliceAI max delta score 0.04.
Sources
spliceai ↗
BP6 No reputable germline database classification supporting benignity was identified because this variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS1 No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant. Details ▾Hide ▴
Still missing
  • No same-amino-acid pathogenic comparator was identified.
PS2 No confirmed de novo occurrence with verified parentage was identified. Details ▾Hide ▴
Still missing
  • No trio or parental testing data were available.
PM5 No evidence was identified showing a different pathogenic missense change at codon 706 that would support PM5. Details ▾Hide ▴
Still missing
  • No codon-matched pathogenic comparator was identified.
PM6 No assumed de novo occurrence was identified. Details ▾Hide ▴
Still missing
  • No parental data were available.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • No family segregation information was available.
PP2 Gene-level missense constraint or a low rate of benign missense variation sufficient for PP2 was not established in the available evidence. Details ▾Hide ▴
Still missing
  • No gene-level missense mechanism assessment was provided.
PP4 No phenotype or family history information was provided that is sufficiently specific to DNMT3A-related disease to support PP4. Details ▾Hide ▴
Still missing
  • No case phenotype data were available.
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to support BS2. Details ▾Hide ▴
Still missing
  • No unaffected carrier data were available.
BS4 No segregation data showing lack of cosegregation were identified. Details ▾Hide ▴
Still missing
  • No family segregation information was available.
BP1 The available evidence does not establish that missense variation is generally a non-disease mechanism for DNMT3A, so BP1 was not applied. Details ▾Hide ▴
Still missing
  • No gene-level evidence supporting BP1 was identified.
BP2 No phase information with another pathogenic variant was identified. Details ▾Hide ▴
Still missing
  • No cis/trans data were available.
BP5 No alternate molecular explanation for disease was identified. Details ▾Hide ▴
Still missing
  • No phenotype-specific alternative cause assessment was available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, p.(Gly706Arg), and it does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice variants. Although loss of function is a supported disease mechanism for DNMT3A, the available PVS1 framework does not support applying PVS1 to this variant type. Details ▾Hide ▴
Evidence considered
  • DNMT3A loss of function is supported as a disease mechanism in the gene-level PVS1 context.
  • The variant-specific PVS1 assessment states that this missense change is outside the generic PVS1 null-variant buckets.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo evidence indicates a recessive disease context or a trans occurrence with another pathogenic variant for this DNMT3A variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis variant is a missense substitution and does not produce a protein length change, so PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant rather than a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DNMT3A
Transcript
NM_022552.4
Coding (HGVS c.)
NM_022552.4:c.2116G>C
Protein (HGVS p.)
NP_072046.2:p.(Gly706Arg)
GRCh38
chr2:25240697 C>G
GRCh37
chr2:25463566 C>G

Gene diagram

Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.

DNMT3ANM_022552.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SupportingComputational 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.971.
  • SpliceAI max delta score 0.04
  • below typical splice-impact concern thresholds.
Sources
spliceai ↗
BP4 Available computational evidence does not support a benign effect. REVEL is 0.971, which argues against BP4, and SpliceAI predicts no meaningful splice effect with a max delta score of 0.04. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.971.
  • SpliceAI max delta score 0.04.
Sources
spliceai ↗
BP7 N/AThis is a missense variant rather than a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.