rs144689354

Variant names:

• chr2-25243931-G-A
• rs144689354
• NM_022552.5:c.1903C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-25243931-G-A
• chr2-25243931-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R635Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2 O:2
• Conservation: PhyloP100: 3.19
• Publications: 57 publications found

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 Gene-Disease associations (from GenCC):

• Tatton-Brown-Rahman overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_022552.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-25243930-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 872724.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.1903C>T	p.Arg635Trp	missense_variant	Exon 16 of 23	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.1903C>T	p.Arg635Trp	missense_variant	Exon 16 of 23	1	NM_022552.5	ENSP00000324375.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000635 AC: 10 AN: 157464 AF XY: 0.0000362

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000819

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 59 AN: 1399786 Hom.: 0 Cov.: 31 AF XY: 0.0000377 AC XY: 26 AN XY: 690454

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000316 AC: 1 AN: 31656

American (AMR) AF: 0.00 AC: 0 AN: 35724

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25176

East Asian (EAS) AF: 0.0000557 AC: 2 AN: 35930

South Asian (SAS) AF: 0.00 AC: 0 AN: 79262

European-Finnish (FIN) AF: 0.0000405 AC: 2 AN: 49332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000445 AC: 48 AN: 1078980

Other (OTH) AF: 0.0000689 AC: 4 AN: 58028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000965 AC: 4 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000744 Hom.: 0

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000305 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

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) -

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

- -

Tatton-Brown-Rahman overgrowth syndrome Pathogenic:1 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
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	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.5	H;.;H;.
PhyloP100		3.2
PrimateAI	Pathogenic	0.91	D
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	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.83
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs144689354; hg19: chr2-25466800; COSMIC: COSV53038925; COSMIC: COSV53038925;