2-25243931-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PP3_ModeratePP5BS2_Supporting

The NM_022552.5(DNMT3A):c.1903C>T(p.Arg635Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,551,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2O:2

Conservation

PhyloP100: 3.19

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 Uncertain_significance. Variant got 4 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 2-25243931-G-A is Pathogenic according to our data. Variant chr2-25243931-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284904.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, other=1, Uncertain_significance=1, Pathogenic=1, not_provided=1}.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5 link	c.1903C>T	p.Arg635Trp	missense_variant	Exon 16 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.1903C>T	p.Arg635Trp	missense_variant	Exon 16 of 23	1	NM_022552.5	ENSP00000324375.5		Q9Y6K1-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000635

AC:

AN:

157464

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

82828

show subpopulations

Gnomad AFR exome

AF:

0.000225

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000864

Gnomad SAS exome

AF:

0.0000438

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000819

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000421

AC:

AN:

1399786

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

690454

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000794

Gnomad4 EAS exome

AF:

0.0000557

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000405

Gnomad4 NFE exome

AF:

0.0000445

Gnomad4 OTH exome

AF:

0.0000689

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000899

Hom.:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000305

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in two unrelated individuals who underwent whole genome sequencing to identify candidate genes in cohorts of patients with autism spectrum disorders; however limited clinical information is available on the probands, and in one proband a second de novo variant in another gene was also identified (Jiang et al., 2013; Yuen et al., 2016); Published functional studies suggest this variant significantly disrupts catalytic activity of DNMT3a (Khrabrova et al., 2019); This variant is associated with the following publications: (PMID: 22077061, 23370706, 26874914, 32269971, 31332282, 21904384, 23507483, 27525107, 28263302, 31981491, 32355762, 33219223, 23849776, 31861499) -

Tatton-Brown-Rahman overgrowth syndrome

Pathogenic:1Uncertain:1

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 635 of the DNMT3A protein (p.Arg635Trp). This variant is present in population databases (rs144689354, gnomAD 0.01%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 23849776, 27525107, 31981491). ClinVar contains an entry for this variant (Variation ID: 284904). 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: 31861499). This variant disrupts the p.Arg635 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32435502; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 24, 2024

Clinical Genetics Laboratory, CHRU Nancy

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 23, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1903C>T (p.R635W) alteration is located in exon 16 (coding exon 15) of the DNMT3A gene. This alteration results from a C to T substitution at nucleotide position 1903, causing the arginine (R) at amino acid position 635 to be replaced by a tryptophan (W). for Tatton-Brown-Rahman syndrome; however, its clinical significance for Heyn-Sproul-Jackson syndrome is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (10/157464) total alleles studied. The highest observed frequency was 0.023% (2/8878) of African alleles. Of note, somatic mosaicism in individuals in general population databases cannot be ruled out as this gene shows evidence of clonal hematopoiesis of indeterminate potential (CHIP). This variant was reported in individual(s) with features consistent with Tatton-Brown-Rahman syndrome; in at least one individual, it was determined to be de novo (DECIPHER; NCBI ClinVar). Another variant at the same codon, c.1904G>A (p.R635Q), has been identified in individual(s) with features consistent with Tatton-Brown-Rahman syndrome (Yokoi, 2020; Cecchi, 2022). Manual reference: National Center for Biotechnology Information. ClinVar; [VCV000284904.15], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000284904.15 (accessed Jan. 23, 2025). This amino acid position is highly conserved in available vertebrate species. In an assay testing DNMT3A function, this variant showed functionally abnormal results (Khrabrova, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Acute myeloid leukemia;C4014545:Tatton-Brown-Rahman overgrowth syndrome;C5231475:Heyn-Sproul-Jackson syndrome

Pathogenic:1

Molecular Genetics Lab, CHRU Brest

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNMT3A-related disorder

Uncertain:1

Jun 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNMT3A c.1903C>T variant is predicted to result in the amino acid substitution p.Arg635Trp. This variant has been reported as a de novo variant in two individuals with autism, but one individual also harbored another de novo variant in another gene, MICALCL (Jiang et al. 2013. PubMed ID: 23849776; Yuen et al. 2017. PubMed ID: 28263302, table S3 genomic position 25466800). In ClinVar, the DNMT3A variant is reported as uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/284904/). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

- -

Autism spectrum disorder;C4014545:Tatton-Brown-Rahman overgrowth syndrome

Other:1

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 09-13-2021 by Lab GeneDx. 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 Dr. Philip Payne 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

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;D;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.5

H;.;H;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.8

D;D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.86

MVP

0.91

MPC

1.1

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.83

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