2-25260014-T-C

Position:

• chr2-25260014-T-C

Variant summary

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

The NM_022552.5(DNMT3A):​c.640-11762A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 152,032 control chromosomes in the GnomAD database, including 17,455 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 0.47 (17455 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.640-11762A>G		intron_variant		ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.640-11762A>G		intron_variant		1	NM_022552.5	P3
DNMT3A	ENST00000264709.7	c.640-11762A>G		intron_variant		1		P3
DNMT3A	ENST00000380756.7	c.640-11762A>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72080 AN: 151914 Hom.: 17429 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.475 AC: 72149 AN: 152032 Hom.: 17455 Cov.: 32 AF XY: 0.479 AC XY: 35630 AN XY: 74312

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.365

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.454

Alfa AF: 0.435 Hom.: 33448

Bravo AF: 0.486

Asia WGS AF: 0.485 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.021
DANN	Benign	0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7594432; hg19: chr2-25482883;