chr2-25269598-A-G

Position:

• chr2-25269598-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022552.5(DNMT3A):​c.639+5343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 151,960 control chromosomes in the GnomAD database, including 7,204 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 0.31 (7204 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.537

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.639+5343T>C		intron_variant		ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.639+5343T>C		intron_variant		1	NM_022552.5	ENSP00000324375	P3
DNMT3A	ENST00000264709.7	c.639+5343T>C		intron_variant		1		ENSP00000264709	P3
DNMT3A	ENST00000380756.7	c.639+5343T>C		intron_variant, NMD_transcript_variant		1		ENSP00000370132

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46437 AN: 151842 Hom.: 7206 Cov.: 31

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.306 AC: 46442 AN: 151960 Hom.: 7204 Cov.: 31 AF XY: 0.306 AC XY: 22713 AN XY: 74290

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.265

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.325

Alfa AF: 0.315 Hom.: 9209

Bravo AF: 0.304

Asia WGS AF: 0.213 AC: 743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13428812; hg19: chr2-25492467;