rs2289195

chr2-25240614-G-A

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.2173+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,611,360 control chromosomes in the GnomAD database, including 135,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13193 hom., cov: 33)
  • Exomes 𝑓: 0.41 (122217 hom.)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.130

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=-0.68).
• BP6: Variant 2-25240614-G-A is Benign according to our data. Variant chr2-25240614-G-A is described in ClinVar as [Benign]. Clinvar id is 1235844.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.2173+26C>T		intron_variant		ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.2173+26C>T		intron_variant		1	NM_022552.5	P3

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62386 AN: 151982 Hom.: 13174 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.411 AC: 102680 AN: 249872 Hom.: 21908 AF XY: 0.403 AC XY: 54462 AN XY: 135040

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.406 AC: 592241 AN: 1459260 Hom.: 122217 Cov.: 35 AF XY: 0.403 AC XY: 292278 AN XY: 725662

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.411 AC: 62441 AN: 152100 Hom.: 13193 Cov.: 33 AF XY: 0.413 AC XY: 30727 AN XY: 74362

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.403

Alfa AF: 0.413 Hom.: 4102

Bravo AF: 0.414

Asia WGS AF: 0.304 AC: 1058 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	-0.68
Cadd	Benign	11
Dann	Benign	0.77
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: rs2289195; hg19: chr2-25463483; COSMIC: COSV53044122; COSMIC: COSV53044122;