2-25282442-C-G

Variant names:

• chr2-25282442-C-G
• NM_022552.5:c.447G>C
• DNMT3A p.Ala149Ala

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_022552.5(DNMT3A):​c.447G>C​(p.Ala149Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT3A NM_022552.5 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.434
• Publications: 0 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: ClinGen, G2P, Orphanet, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=0.434 with no splicing effect.

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.447G>C	p.Ala149Ala	splice_region synonymous	Exon 4 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.447G>C	p.Ala149Ala	splice_region synonymous	Exon 4 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320892.2		c.447G>C	p.Ala149Ala	synonymous	Exon 4 of 4	NP_001307821.1	Q9Y6K1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.447G>C	p.Ala149Ala	splice_region synonymous	Exon 4 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.447G>C	p.Ala149Ala	splice_region synonymous	Exon 4 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000406659.3	TSL:1	c.447G>C	p.Ala149Ala	synonymous	Exon 4 of 4	ENSP00000384852.3	Q9Y6K1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		0.43
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-25505311;