2-25266314-G-C

Variant names:

• chr2-25266314-G-C
• rs7590760
• NM_022552.5:c.639+8627C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022552.5(DNMT3A):​c.639+8627C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,058 control chromosomes in the GnomAD database, including 19,189 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19189 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280
• Publications: 16 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

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.639+8627C>G		intron	N/A	NP_072046.2
	DNMT3A	NM_175629.2		c.639+8627C>G		intron	N/A	NP_783328.1	Q9Y6K1-1
	DNMT3A	NR_135490.2		n.870+8627C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.639+8627C>G		intron	N/A	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.639+8627C>G		intron	N/A	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380756.7	TSL:1	n.639+8627C>G		intron	N/A	ENSP00000370132.3	F8WE91

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75624 AN: 151940 Hom.: 19188 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.504

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75652 AN: 152058 Hom.: 19189 Cov.: 32 AF XY: 0.494 AC XY: 36734 AN XY: 74332

African (AFR) AF: 0.493 AC: 20431 AN: 41466

American (AMR) AF: 0.397 AC: 6071 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1619 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1786 AN: 5170

South Asian (SAS) AF: 0.398 AC: 1916 AN: 4816

European-Finnish (FIN) AF: 0.524 AC: 5534 AN: 10568

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36627 AN: 67976

Other (OTH) AF: 0.500 AC: 1055 AN: 2112

Alfa AF: 0.388 Hom.: 1050

Bravo AF: 0.486

Asia WGS AF: 0.340 AC: 1188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.2
DANN	Benign	0.74
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs7590760; hg19: chr2-25489183;