2-25235677-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022552.5(DNMT3A):c.2597+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,579,922 control chromosomes in the GnomAD database, including 246,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (18032 hom., cov: 32)
  • Exomes 𝑓: 0.56 (228680 hom.)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.83

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-25235677-C-T is Benign according to our data. Variant chr2-25235677-C-T is described in ClinVar as [Benign]. Clinvar id is 1220822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.2597+30G>A		intron_variant		ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.2597+30G>A		intron_variant		1	NM_022552.5	P3

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69097 AN: 151942 Hom.: 18029 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.514 AC: 127888 AN: 248918 Hom.: 34698 AF XY: 0.519 AC XY: 69932 AN XY: 134630

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.559 AC: 798739 AN: 1427862 Hom.: 228680 Cov.: 23 AF XY: 0.558 AC XY: 397266 AN XY: 711626

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.539

Gnomad4 ASJ exome AF: 0.484

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.603

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.455 AC: 69116 AN: 152060 Hom.: 18032 Cov.: 32 AF XY: 0.453 AC XY: 33708 AN XY: 74342

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.603

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.479

Alfa AF: 0.556 Hom.: 48940

Bravo AF: 0.439

Asia WGS AF: 0.354 AC: 1235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.52
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304429; hg19: chr2-25458546; COSMIC: COSV53040530; COSMIC: COSV53040530;