Genetic Information

Gene & Transcript Details

Gene
DNMT3A
Transcript
NM_022552.4 MANE Select
Total Exons
—
Reference Sequence
NC_000002.11
Alternative Transcripts
IDStatusDetails
NM_022552.4 RefSeq Select 4324 nt | 268–3006
NM_022552.5 MANE Select 9421 nt | 278–3016
NM_022552.3 Alternative 4314 nt | 258–2996

Variant Details

HGVS Notation
NM_022552.4:c.977G>T
Protein Change
R326L
Location
Exon 8 (Exon 8 of )
8
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.000796 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Unknown
0 publications
Clinical Statement

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COSMIC Somatic Evidence

Open
COSMIC ID
COSM6929654
Recurrence
4 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene DNMT3A.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: DNMT3AR326LDNMT3AR326LSomaticNCBI Gene:1788|Show additional gene information Variant OverviewDNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies.The DNMT3A R326L mutation has not specifically been reviewed by the OncoKB team. However, DNMT3A R326S is likely oncogenic, and therefore DNMT3A R326L is considered likely oncogenic.Hide mutation effect description The DNMT3A R326L mutation has not specifically been reviewed by the OncoKB team. However, the mutation effect description for DNMT3A R326S, an alternate allele of DNMT3A R326L, is: The DNMT3A R326S mutation is located in the PWWP domain of the protein. This mutation has been identified in acute lymphoblastic T-cell leukemia (PMID: 23341344). In vitro studies with HEK293T cells expressing DNMT3A R326S demonstrate that the mutation is inactivating as measured by reduced methyltransferase function and protein stability compared to wildtype (PMID: 34429321). JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

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Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Mixed/VUS
PP3 Applied
No
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.02 54 bp
- Donor Loss (DL) 0.02 -37 bp
+ Acceptor Gain (AG) 0.0 -21 bp
+ Donor Gain (DG) 0.0 416 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PS3

PS3 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

BP4

BP4 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)