rs144689354

chr2-25243931-G-Achr2-25243931-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1 PM5 PP3_Moderate PP5 BS2

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). 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:3 U:1 O:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• 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: {not_provided=1, Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.1903C>T	p.Arg635Trp	missense_variant	16/23	ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.1903C>T	p.Arg635Trp	missense_variant	16/23	1	NM_022552.5	P3

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

GnomAD3 exomes AF: 0.0000635 AC: 10 AN: 157464 Hom.: 0 AF XY: 0.0000362 AC XY: 3 AN XY: 82828

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

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

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.: 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:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2021	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) -

Acute myeloid leukemia;C4014545:Tatton-Brown-Rahman overgrowth syndrome;C5231475:Heyn-Sproul-Jackson syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

-

- -

Tatton-Brown-Rahman overgrowth syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

Autism spectrum disorder;C4014545:Tatton-Brown-Rahman overgrowth syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

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
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;.
MutationTaster	Benign	1.0	D;D;D;D
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

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

Other links and lift over

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