rs749131

Positions:

• chr2-25306755-A-C

Variant summary

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

The NM_022552.5(DNMT3A):​c.73-6512T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,022 control chromosomes in the GnomAD database, including 21,547 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 0.53 (21547 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.668

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.73-6512T>G		intron_variant		ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.73-6512T>G		intron_variant		1	NM_022552.5	ENSP00000324375	P3
DNMT3A	ENST00000264709.7	c.73-6512T>G		intron_variant		1		ENSP00000264709	P3
DNMT3A	ENST00000406659.3	c.73-6512T>G		intron_variant		1		ENSP00000384852
DNMT3A	ENST00000380756.7	c.73-6512T>G		intron_variant, NMD_transcript_variant		1		ENSP00000370132

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80372 AN: 151904 Hom.: 21526 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.524

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

GnomAD4 genome AF: 0.529 AC: 80431 AN: 152022 Hom.: 21547 Cov.: 32 AF XY: 0.524 AC XY: 38903 AN XY: 74312

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.518

Alfa AF: 0.524 Hom.: 3578

Bravo AF: 0.519

Asia WGS AF: 0.350 AC: 1220 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.72
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749131; hg19: chr2-25529624;