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NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 6, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000623601.5

Allele description [Variation Report for NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)]

NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)

Gene:
DNMT3A:DNA methyltransferase 3 alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p23.3
Genomic location:
Preferred name:
NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)
HGVS:
  • NC_000002.12:g.25234373C>T
  • NG_029465.2:g.113218G>A
  • NM_001320893.1:c.2189G>A
  • NM_001375819.1:c.1976G>A
  • NM_022552.5:c.2645G>AMANE SELECT
  • NM_153759.3:c.2078G>A
  • NM_175629.2:c.2645G>A
  • NP_001307822.1:p.Arg730His
  • NP_001362748.1:p.Arg659His
  • NP_072046.2:p.Arg882His
  • NP_715640.2:p.Arg693His
  • NP_783328.1:p.Arg882His
  • LRG_459t2:c.2078G>A
  • LRG_459t4:c.2645G>A
  • LRG_459:g.113218G>A
  • LRG_459p2:p.Arg693His
  • LRG_459p4:p.Arg882His
  • NC_000002.11:g.25457242C>T
  • NM_022552.4:c.2645G>A
  • NM_022552.5:c.2645G>A
  • NM_175629.1:c.2645G>A
  • NR_135490.2:n.3075G>A
Protein change:
R659H; ARG882HIS
Links:
OMIM: 602769.0006; dbSNP: rs147001633
NCBI 1000 Genomes Browser:
rs147001633
Molecular consequence:
  • NM_001320893.1:c.2189G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375819.1:c.1976G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022552.5:c.2645G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153759.3:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_175629.2:c.2645G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_135490.2:n.3075G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000740689Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Oct 6, 2022) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

DNMT3A mutations in acute myeloid leukemia.

Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, et al.

N Engl J Med. 2010 Dec 16;363(25):2424-33. doi: 10.1056/NEJMoa1005143. Epub 2010 Nov 10.

PubMed [citation]
PMID:
21067377
PMCID:
PMC3201818

The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.

Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R, Meyer MR, Erdmann-Gilmore P, Townsend RR, Wilson RK, Ley TJ.

Cancer Cell. 2014 Apr 14;25(4):442-54. doi: 10.1016/j.ccr.2014.02.010. Epub 2014 Mar 20.

PubMed [citation]
PMID:
24656771
PMCID:
PMC4018976
See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000740689.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

The c.2645G>A (p.R882H) alteration is located in exon 23 (coding exon 22) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 2645, causing the arginine (R) at amino acid position 882 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.023% (64/282404) total alleles studied. The highest observed frequency was 0.055% (11/19926) of East Asian alleles. Additionally, this alteration has also been observed to occur sporadically in the population and proposed to be an early mutation in cancer initiation (Ley, 2010: Russler-Germain, 2014). Somatic mosaicism in individuals in general population databases cannot be ruled out. This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of Tatton-Brown-Rahman syndrome, some of which later developed hematopoietic malignancies (Kosaki, 2017; Shen, 2017; Balci, 2020; Ferris, 2022; DECIPHER v.9.32). This alteration has been well described as a somatically acquired mutation associated with acute myeloid leukemia. It accounts for approximately 50% of all somatic DNMT3A mutations observed in AML cells (Ley, 2010, Russler-Germain, 2014). This nucleotide position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024