NM_022552.5:c.645G>C

Variant names:

• chr2-25248247-C-G
• rs587778238
• NM_022552.5:c.645G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022552.5(DNMT3A):​c.645G>C​(p.Glu215Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E215E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.84
• Publications: 2 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: Orphanet, Illumina, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41372254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	NM_022552.5	MANE Select	c.645G>C	p.Glu215Asp	missense	Exon 7 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.645G>C	p.Glu215Asp	missense	Exon 7 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.189G>C	p.Glu63Asp	missense	Exon 2 of 18	NP_001307822.1	Q9Y6K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.645G>C	p.Glu215Asp	missense	Exon 7 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.645G>C	p.Glu215Asp	missense	Exon 7 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.78G>C	p.Glu26Asp	missense	Exon 3 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Tatton-Brown-Rahman overgrowth syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.023	D
Sift4G	Benign	0.11	T
Polyphen		0.96	P
Vest4		0.42
MutPred		0.38		Loss of sheet (P = 0.0037)
MVP		0.86
MPC		1.1
ClinPred		0.77	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.56
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs587778238; hg19: chr2-25471116;