rs2276598

chr2-25246633-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022552.5(DNMT3A):c.1266G>A(p.Leu422=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,612,420 control chromosomes in the GnomAD database, including 25,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3635 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21645 hom.)
• Consequence: DNMT3A NM_022552.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.673

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-25246633-C-T is Benign according to our data. Variant chr2-25246633-C-T is described in ClinVar as [Benign]. Clinvar id is 1164958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.673 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.1266G>A	p.Leu422=	synonymous_variant	10/23	ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.1266G>A	p.Leu422=	synonymous_variant	10/23	1	NM_022552.5	P3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31799 AN: 152058 Hom.: 3622 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.190 AC: 47115 AN: 247968 Hom.: 4890 AF XY: 0.183 AC XY: 24644 AN XY: 134780

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.315

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.168 AC: 244632 AN: 1460242 Hom.: 21645 Cov.: 34 AF XY: 0.166 AC XY: 120277 AN XY: 726354

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.209 AC: 31839 AN: 152178 Hom.: 3635 Cov.: 33 AF XY: 0.211 AC XY: 15714 AN XY: 74420

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.185

Alfa AF: 0.183 Hom.: 1468

Bravo AF: 0.212

Asia WGS AF: 0.249 AC: 864 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tatton-Brown-Rahman overgrowth syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	6.9
Dann	Benign	0.80

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: rs2276598; hg19: chr2-25469502; COSMIC: COSV53040646; COSMIC: COSV53040646;