DNMT3A p.Leu422Leu

Variant names:

• chr2-25246632-C-C
• NM_022552.5:c.

Your query was ambiguous. Multiple possible variants found:

• chr2-25246633--
• chr2-25246635-G-A
• chr2-25246633-C-A
• chr2-25246633-C-G
• chr2-25246633-C-T
• chr2-25246633-CAG-TAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022552.5(DNMT3A):​c. variant causes a exon region change involving the alteration of a non-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: 33)
• Consequence: DNMT3A NM_022552.5 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.673
• 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: 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 2 ACMG points.

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

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.		exon_region	Exon 10 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.		exon_region	Exon 10 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.		exon_region	Exon 5 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.		exon_region	Exon 10 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.		exon_region	Exon 10 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.		exon_region	Exon 6 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67

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: chr2-25469501;