rs377577594

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_022552.5(DNMT3A):c.2644C>T(p.Arg882Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R882H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 10.0

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 13 ACMG points.

PM1

In a domain SAM-dependent MTase C5-type (size 278) in uniprot entity DNM3A_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_022552.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-25234373-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

PP5

Variant 2-25234374-G-A is Pathogenic according to our data. 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. Variant chr2-25234374-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5 link	c.2644C>T	p.Arg882Cys	missense_variant	Exon 23 of 23	ENST00000321117.10	NP_072046.2	Q9Y6K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10 link	c.2644C>T	p.Arg882Cys	missense_variant	Exon 23 of 23	1	NM_022552.5	ENSP00000324375.5		Q9Y6K1-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251136

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000149

AC:

218

AN:

1461066

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000158

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000793

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tatton-Brown-Rahman overgrowth syndrome

Pathogenic:6

Apr 01, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg882Cys variant in DNMT3A has been reported as a de novo germline occurrence in 4 individuals with Tatton-Brown-Rahman syndrome, one of who developed acute myeloid leukemia, (Tlemsani 2016, Hollink 2017, Shen 2017) and is one of the most common somatic DNMT3A variants in acute myeloid leukemia. It has also been identified in 3/10364 Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, the median variant allele fraction in these individuals was rather low, suggesting they might be associated with age-related clonal hematopoiesis. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, and in vitro functional studies support an impact on protein function (Russler-Germain 2014). An additional variant involving this codon p.Arg882His has been identified in individuals with Tatton Brown-Rahman syndrome and is a commonly identified somatic variant in acute myeloid leukemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Tatton-Brown-Rahman syndrome (also known as tall stature-intellectual disability-facial dysmorphism syndrome). ACMG/AMP Criteria applied: PM6_Strong, PS2, PS3_Moderate, PS4_Moderate, PP3. -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with disease. Loss of function has been associated with Tatton-Brown-Rahman syndrome (MIM#615879) while gain of function has been associated with Heyn-Sproul-Jackson syndrome (MIM#618724) and demonstrated for two missense variants (PMID: 30478443). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (34 heterozygotes, 0 homozygotes). However, it is likely somatic in the majority of those heterozygotes due to the low allele balance. (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 64 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. p.Arg882 is well reported to be a hotspot for both germline variants causing TBRS and somatic variants in acute myeloid leukaemia (ClinVar, PMID: 28941052). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least two alternative changes (p.(Arg882His) and p.(Arg882Ser)) have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and p.(Arg882His) has been reported in several individuals with TBRS or syndromic intellectual disability (DECIPHER, PMIDs: 28941052, 29900417). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and observed as de novo in at least seven individuals with TBRS (PMIDs: 28941052, 27317772, 28432085, 29900417). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 05, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo missense variant c.2644C>T, p.Arg882Cys identified in the DNMT3A gene has been reported in multiple patients with Tatton-Brown-Rahman syndrome (PubMed: 28941052, 28432085, 31961069). This variant has 24 heterozygotes (0.016%) in gnomAD v3.1.1, suggesting moderate allele frequency in the populations represented in this database. However, researchers revealed that the median variant allele fraction in individuals reported in the population database with this variant was ~19%, strongly suggesting that the observed frequencies are confounding somatic variants in individuals with age-related clonal hematopoiesis (PMID: 28229513). In silico algorithms predict a deleterious effect, and the variant resides at the C-5 cytosine-specific DNA methylase (Dnmt) domain of the DNMT3A protein. Based on the available evidence, the de novo missense variant c.2644C>T, p.Arg882Cys in the DNMT3A gene is classified as pathogenic. -

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 882 of the DNMT3A protein (p.Arg882Cys). 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 syndrome (PMID: 27317772, 28432085). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375882). 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: 31620784). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNMT3A: PS2, PM1, PM5, PS4:Moderate, PP3 -

Aug 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 23741974, 21859430, 35861108, 33057194, 35982159, 33878367, 22829128, 28432085, 28941052, 27317772, 34788385) -

Acute myeloid leukemia

Pathogenic:2

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

DNMT3A-related disorder

Pathogenic:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNMT3A c.2644C>T variant is predicted to result in the amino acid substitution p.Arg882Cys. This variant was reported as a de novo variant in two patients with Sotos-like syndrome (Tlemsani et al. 2016. PubMed ID: 27317772), in one patient with Tatton–Brown–Rahman syndrome (see patient 3, Shen et al. 2017. PubMed ID: 28941052), and in another patient with Tatton-Brown-Rahman syndrome, who developed acute myeloid leukaemia (Hollink et al. 2017. PubMed ID: 28432085). This variant was also reported in one patient with lung cancer (Li et al. 2021. PubMed ID: 33878367). Somatic variants, primarily missense, involving amino acid residue p.Arg882, but also other nonsense and protein-truncating variants, have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients (Im et al. 2014. PubMed ID: 24699305, Ley et al. 2010. PubMed ID: 21067377). In summary, we classify this variant as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jun 04, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder

Pathogenic:1

Aug 06, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EBV-positive nodal T- and NK-cell lymphoma

Pathogenic:1

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;D;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.5

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.76

MVP

0.83

MPC

1.5

ClinPred

0.38

GERP RS

5.7

Varity_R

0.94

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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