2-25234373-C-T

Position:

chr2-25234373-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_022552.5(DNMT3A):c.2645G>A(p.Arg882His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R882G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:2

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

DNMT3A (HGNC:2978): (DNA methyltransferase 3 alpha) CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]

DNMT3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a helix (size 8) in uniprot entity DNM3A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_022552.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-25234374-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 375882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 2-25234373-C-T is Pathogenic according to our data. Variant chr2-25234373-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25234373-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38679647). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5 linkuse as main transcript	c.2645G>A	p.Arg882His	missense_variant	23/23	ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10 linkuse as main transcript	c.2645G>A	p.Arg882His	missense_variant	23/23	1	NM_022552.5	P3	Q9Y6K1-1

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251040

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000254

AC:

371

AN:

1460500

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

726560

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000575

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.000257

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000369

AC:

AN:

151936

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.000508

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000509

Hom.:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 31, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 16, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center	Jun 08, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 06, 2021	- -
-, no assertion criteria provided	clinical testing	Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health	Jan 24, 2024	This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. -

Tatton-Brown-Rahman overgrowth syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 882 of the DNMT3A protein (p.Arg882His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732, 28252636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT3A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 13, 2023	The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene was identified at low variant allele frequency (4/26 reads, 15%VAF), and may represent a low level mosaic germline variant or an acquired somatic variant. The c.2645G>A, p.(Arg882His) variant in the DNMT3A gene is a well known Pathogenic variant and has been identified in multiple individuals with Tatton-Brown-Rahman syndrome [PMID: 29900417, 27991732, 28941052, others], and is also often identified as a somatic variant in Acute Myeloid Leukemia cells [PMID:21067377, 24656771, 35771960, others]. Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others]. The c.2645G>A, p.(Arg882His) variant identified in the DNMT3A gene is reported as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2022	Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); Reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28667884, 30185810, 34788385, 24656771, 24497509, 27991732, 29349042, 29518238, 30245403, 28643785, 30017658, 28475857, 27701732, 28386848, 28941052, 31961069, 28252636) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2022	- -

Clonal Cytopenia of Undetermined Significance

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetic Pathology Unit, University Of Rochester Medical Center

- -

Myelodysplastic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Jun 25, 2024

This variant has been reported as a de novo event in multiple unrelated individuals with Tatton-Brown–Rahman syndrome, as well as other missense variant in the same residue (https://pubmed.ncbi.nlm.nih.gov/28941052/ ; https://pubmed.ncbi.nlm.nih.gov/34788385/). Codon 882 is considered a mutational hotspot for both somatic events in hematological neoplasias and for constitutional mutations leading to TBRS. Population data for this variant is unreliable as it might be the result of postzygotic clonal hematopoiesis Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/). Therefore we interpret it as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

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. -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Abnormality of the nervous system

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Intellectual disability

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2020

The p.Arg882His variant in DNMT3A has been reported in 2 heterozygous individuals (one de novo) with Tatton-Brown-Rahman syndrome, one of who also developed acute myelogenous leukemia (Kosaki 2018 PMID: 27991732, Hollink 2017 PMID: 28432085). It has been reported in ClinVar (Variation ID 375881) and identified in 0.055% (11/19926) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg882Cys) has been identified in 2 individuals (de novo) with Tatton-Brown-Rahman syndrome and this residue (Arg882) (including p.Arg882His) is the most frequent DNMT3A somatic mutation hotspot in AML (Tlemsani 2016 PMID: 27317772, Kosaki 2018 PMID: 27991732). In vitro functional studies further support an impact on protein function (Russler-Germain 2014 PMID: 24656771). It is possible that some DNMT3A variants may actually represent postzygotic clonal hematopoiesis rather than constitutional variants (see PMID 27546487; 25426838). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome. ACMG/AMP Criteria applied: PS2, PP3, PM5, PS3_Supporting, PS4_Supporting. -

EBV-positive nodal T- and NK-cell lymphoma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Pathology, School of Medicine, Fujita Health University

- -

DNMT3A-related disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

Variant interpreted as Uncertain significance and reported on 04-14-2015 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.;D;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.3

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.050

T;T;T;T

Polyphen

0.65

P;.;P;.

Vest4

0.65

MVP

0.56

MPC

1.4

ClinPred

0.82

GERP RS

5.7

Varity_R

0.84

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over