chr2-25234289-G-T

Variant names:

• chr2-25234289-G-T
• NM_022552.5:c.2729C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_022552.5(DNMT3A):​c.2729C>A​(p.Ala910Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.2729C>A	p.Ala910Glu	missense_variant	Exon 23 of 23	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.2729C>A	p.Ala910Glu	missense_variant	Exon 23 of 23	1	NM_022552.5	ENSP00000324375.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;D;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L;.;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	D;.;D;.
Vest4		0.68
MutPred		0.37		Gain of disorder (P = 0.0031);.;Gain of disorder (P = 0.0031);.;
MVP		0.75
MPC		1.3
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-25457158;