DNMT3Ac.977G>TNot classified

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Variant interpretation report

DNMT3A c.977G>T, p.(Arg326Leu)

NM_022552.4:c.977G>T NP_072046.2:p.(Arg326Leu) View identifiers

Classification

Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About DNMT3A

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 11 May 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (moderate): This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 0.00080% (2/251356 alleles) and gnomAD v4.1 AF 0.00031% (5/1614064 alleles), both below the 0.1% PM2 threshold.
PP3 (supporting): Computational evidence supports a deleterious missense effect. REVEL is 0.723 and BayesDel is 0.244335, both consistent with a damaging protein effect, while SpliceAI predicts no significant splice impact (max delta score 0.00).

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 present at very low frequency in population databases, with gnomAD v2.1 AF 0.00080% (2/251356 alleles) and gnomAD v4.1 AF 0.00031% (5/1614064 alleles), both below the 0.1% PM2 threshold.

PP3Supporting

PP3 · supporting

Computational evidence supports a deleterious missense effect. REVEL is 0.723 and BayesDel is 0.244335, both consistent with a damaging protein effect, while SpliceAI predicts no significant splice impact (max delta score 0.00).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Not classified

No source classification-combination explanation was recorded.

02The sources

Evidence at a glance

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

gnomAD v4.1

gnomAD v2.1

Population frequency

5 / 1,614,064 alleles

gnomAD v4.1: 5 / 1,614,064 alleles. Recorded AF 3.09777e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.95684e-06; MAF= 0.00080%, 2/251356 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000162866; MAF= 0.01629%, 1/6140 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53064654, n = 2 times).

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 · 5 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The DNMT3A c.977G>T (p.Arg326Leu; p.R326L) variant has not been reported in ClinVar.

This variant is present at very low frequency in gnomAD, with AF 0.00080% (2/251356 alleles) in v2.1 and AF 0.00031% (5/1614064 alleles) in v4.1, both below the 0.1% PM2 threshold.

Computational evidence supports a deleterious missense effect, with REVEL 0.723 and BayesDel 0.244335, while SpliceAI predicts no significant splice impact (max delta score 0.00).

Met · 2

PM2 ModerateThis variant is present at very low frequency in population databases, with gnomAD v2.1 AF 0.00080% (2/251356 alleles) and gnomAD v4.1 AF 0.00031% (5/1614064 alleles), both below the 0.1% PM2 threshold. Details ▾Hide ▴

Rule

Evidence considered

gnomAD v2.1 total AF 7.95684e-06
gnomAD v4.1 total AF 3.09777e-06

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.723 and BayesDel is 0.244335, both consistent with a damaging protein effect, while SpliceAI predicts no significant splice impact (max delta score 0.00). Details ▾Hide ▴

Rule

Evidence considered

REVEL 0.723
BayesDel 0.244335
SpliceAI max delta score 0.00

Sources

revelbayesdelspliceai ↗

Not met · 5 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant hotspot, and available evidence is insufficient to show that codon 326 is within a mutational hotspot or other well-established critical region without benign variation for generic PM1 use. Details ▾Hide ▴

Rule

Evidence considered

Cancer Hotspots review did not identify a significant hotspot at this residue.

Still missing

No established hotspot or codon-specific pathogenic enrichment was identified.

Sources

hotspots ↗

BA1 Population frequency does not meet the benign stand-alone threshold. The highest observed population frequency is 0.01629% in gnomAD v2.1 Remaining individuals and 0.00223% in gnomAD v4.1 East Asian, both below the 1% BA1 threshold. Details ▾Hide ▴

Rule

Evidence considered

gnomAD v2.1 highest observed subpopulation AF 0.000162866
gnomAD v4.1 highest observed subpopulation AF 2.22826e-05

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Population frequency is below the benign strong threshold. The highest observed population frequency is 0.01629% in gnomAD v2.1 and 0.00223% in gnomAD v4.1, both below the 0.3% BS1 threshold. Details ▾Hide ▴

Rule

Evidence considered

gnomAD v2.1 best subpopulation AF 0.000162866
gnomAD v4.1 best subpopulation AF 2.22826e-05

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 Available population data do not show this variant at a frequency or zygosity pattern sufficient to support observation in healthy adults for BS2. Details ▾Hide ▴

Rule

Evidence considered

No homozygotes were reported in gnomAD v2.1 or v4.1.

Still missing

Robust evidence of unaffected adult carriers was not identified.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 Computational evidence does not support a benign effect. REVEL 0.723 and BayesDel 0.244335 are consistent with a damaging missense effect, although SpliceAI predicts no significant splice impact (max delta score 0.00). Details ▾Hide ▴

Rule

Evidence considered

REVEL 0.723
BayesDel 0.244335
SpliceAI max delta score 0.00

Sources

revelbayesdelspliceai ↗

Not assessed · 16 · no assessment recorded

PS1 No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic interpretation. Details ▾Hide ▴

Rule

Still missing

A confirmed same-amino-acid pathogenic comparator was not identified.

PS2 No de novo occurrence data were identified for this variant. Details ▾Hide ▴

Rule

Still missing

A proband-level report with confirmed maternity and paternity was not identified.

PS3 Available evidence does not include a well-established functional study demonstrating a damaging effect for p.Arg326Leu. The identified publications provide gene-level DNMT3A functional context but do not document a validated variant-specific assay result for this substitution. Details ▾Hide ▴

Rule

Evidence considered

OncoKB linked DNMT3A functional literature.
No variant-specific assay result for p.Arg326Leu was captured.

Still missing

A validated variant-specific functional assay result was not identified.

Sources

oncokb ↗PMID:23341344 ↗PMID:34429321 ↗

PS4 No affected-case enrichment or case-control data were identified for this variant. Details ▾Hide ▴

Rule

Evidence considered

ClinVar has no record for this variant.
Population data show rarity but do not establish case enrichment.

Still missing

Independent affected observations or formal enrichment data were not identified.

Sources

clinvar ↗gnomad_v2 ↗gnomad_v4 ↗

PM3 No phase data or recessive-case evidence were identified for this variant. Details ▾Hide ▴

Rule

Still missing

Trans observations with a pathogenic variant were not identified.

PM6 No presumed de novo report was identified for this variant. Details ▾Hide ▴

Rule

Still missing

A de novo occurrence lacking full parental confirmation was not identified.

PP1 No segregation data were identified for this variant. Details ▾Hide ▴

Rule

Still missing

Informative family segregation evidence was not identified.

PP2 Available evidence does not establish a gene-specific missense constraint rule suitable for applying PP2 in this case. Details ▾Hide ▴

Rule

Still missing

A validated gene-level PP2 framework was not identified.

PP4 No phenotype-specific clinical data were provided to assess whether the presentation is highly specific for a DNMT3A-related disorder. Details ▾Hide ▴

Rule

Still missing

Phenotypic specificity data were not available.

PP5 No reputable external pathogenic classification for this exact variant was identified. Details ▾Hide ▴

Rule

Evidence considered

ClinVar has no entry for this variant.

Still missing

An external pathogenic assertion for this exact variant was not identified.

Sources

clinvar ↗

BS3 Available evidence does not include a well-established functional study demonstrating normal function for p.Arg326Leu. Details ▾Hide ▴

Rule

Evidence considered

Identified publications provide gene-level context but not a normal-function result for this variant.

Still missing

A validated variant-specific benign functional assay result was not identified.

Sources

oncokb ↗PMID:23341344 ↗PMID:34429321 ↗

BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴

Rule

Still missing

Informative family data showing lack of segregation were not identified.

BP1 Available evidence does not support treating missense change as a low-prior mechanism for this gene in a way that would justify BP1. Details ▾Hide ▴

Rule

Still missing

A gene-level BP1 framework was not identified.

BP2 No phase data were identified to assess BP2. Details ▾Hide ▴

Rule

Still missing

In trans or in cis observations with another variant were not identified.

BP5 No alternative molecular explanation was provided that would account for the phenotype independently of this variant. Details ▾Hide ▴

Rule

Still missing

An alternate established cause for the phenotype was not available for review.

BP6 No reputable external benign classification for this exact variant was identified. Details ▾Hide ▴

Rule

Evidence considered

ClinVar has no entry for this variant.

Still missing

An external benign assertion for this exact variant was not identified.

Sources

clinvar ↗

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant, and available evidence does not indicate a nonsense, frameshift, canonical +/-1 or 2 splice, or other established loss-of-function consequence. SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not applicable. Details ▾Hide ▴

Rule

Evidence considered

DNMT3A loss of function is an established germline disease mechanism at the gene level.
The variant-specific PVS1 scaffold does not place this change in a generic null-variant bucket.
SpliceAI max delta score is 0.00.

Sources

pvs1_gene_contextpvs1_variant_assessmentspliceai ↗pvs1_generic_framework

PM4 N/AThis is not a protein length-changing variant. Details ▾Hide ▴

Rule

PM5 N/AClassic same-residue PM5 use could not be confirmed safely for this case, and no established same-residue pathogenic comparator was identified for application here. Details ▾Hide ▴

Rule

Evidence considered

PM5 candidate review did not confirm eligibility for classic same-residue PM5 logic.

Sources

pm5_candidates

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

Rule

BP7 N/AThis criterion is intended for synonymous or certain intronic variants and is not applicable to this missense change. Details ▾Hide ▴

Rule

Identifiers

Gene: DNMT3A
Transcript: NM_022552.4
Coding (HGVS c.): NM_022552.4:c.977G>T
Protein (HGVS p.): NP_072046.2:p.(Arg326Leu)
GRCh38: chr2:25247628 C>A
GRCh37: chr2:25470497 C>A
COSMIC: COSV53064654

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in DNMT3A — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 5 / 1,614,064 alleles AF 3.1e-06 · 0 homozygotes

gnomAD v2.1 2 / 251,356 alleles AF 7.96e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,614,064 alleles · 0 hom

East Asian1 / 44,878	2.2e-05
Admixed American1 / 60,004	1.7e-05
Remaining individuals1 / 62,504	1.6e-05
South Asian1 / 91,078	1.1e-05
European (non-Finnish)1 / 1,179,974	8.5e-07

0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,356 alleles · 0 hom

Remaining individuals1 / 6,140	0.00016
East Asian1 / 18,394	5.4e-05

0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.09777e-06; MAF= 0.00031%, 5/1614064 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22826e-05; MAF= 0.00223%, 1/44878 alleles, homozygotes = 0).

gnomAD v2.1

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.000

Other predictors

REVEL: 0.723
BayesDel: 0.244

How the predictions were used

Rule

Evidence considered

REVEL 0.723
BayesDel 0.244335
SpliceAI max delta score 0.00

Sources

revelbayesdelspliceai ↗

Rule

Evidence considered

REVEL 0.723
BayesDel 0.244335
SpliceAI max delta score 0.00

Sources

revelbayesdelspliceai ↗

BP7 N/AThis criterion is intended for synonymous or certain intronic variants and is not applicable to this missense change. Details ▾Hide ▴

Rule

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL.

No paper-specific finding is recorded.

PMID 23341344 ↗
Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor.

No paper-specific finding is recorded.

PMID 34429321 ↗

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

gnomAD v4.1 5 / 1,614,064 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 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

gnomAD v2.1

ClinVar

This variant is absent from ClinVar.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV53064654, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.