2-25234299-C-CCTT

Variant names:

• chr2-25234299-C-CCTT
• rs769590067
• NM_022552.5:c.2716_2718dupAAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_022552.5(DNMT3A):​c.2716_2718dupAAG​(p.Lys906dup) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT3A NM_022552.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_022552.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_022552.5. Strenght limited to Supporting due to length of the change: 1aa.

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.2716_2718dupAAG	p.Lys906dup	conservative_inframe_insertion	Exon 23 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.2716_2718dupAAG	p.Lys906dup	conservative_inframe_insertion	Exon 23 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.2260_2262dupAAG	p.Lys754dup	conservative_inframe_insertion	Exon 18 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.2716_2718dupAAG	p.Lys906dup	conservative_inframe_insertion	Exon 23 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.2716_2718dupAAG	p.Lys906dup	conservative_inframe_insertion	Exon 23 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.2149_2151dupAAG	p.Lys717dup	conservative_inframe_insertion	Exon 19 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

Splicing

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

Other links and lift over

dbSNP: rs769590067; hg19: chr2-25457168;