rs2276598

Variant names:

• chr2-25246633-C-T
• rs2276598
• NM_022552.5:c.1266G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022552.5(DNMT3A):​c.1266G>A​(p.Leu422Leu) 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:3
• Conservation: PhyloP100: 0.673
• Publications: 31 publications found

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]

DNMT3A Gene-Disease associations (from GenCC):

• Tatton-Brown-Rahman overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.1266G>A	p.Leu422Leu	synonymous_variant	Exon 10 of 23	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.1266G>A	p.Leu422Leu	synonymous_variant	Exon 10 of 23	1	NM_022552.5	ENSP00000324375.5

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

GnomAD2 exomes AF: 0.190 AC: 47115 AN: 247968 AF XY: 0.183

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 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

African (AFR) AF: 0.299 AC: 9996 AN: 33434

American (AMR) AF: 0.202 AC: 9013 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5161 AN: 26080

East Asian (EAS) AF: 0.287 AC: 11393 AN: 39678

South Asian (SAS) AF: 0.119 AC: 10280 AN: 86232

European-Finnish (FIN) AF: 0.217 AC: 11408 AN: 52556

Middle Eastern (MID) AF: 0.116 AC: 671 AN: 5760

European-Non Finnish (NFE) AF: 0.158 AC: 175976 AN: 1111518

Other (OTH) AF: 0.178 AC: 10734 AN: 60338

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

African (AFR) AF: 0.292 AC: 12114 AN: 41508

American (AMR) AF: 0.178 AC: 2723 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1630 AN: 5158

South Asian (SAS) AF: 0.130 AC: 627 AN: 4830

European-Finnish (FIN) AF: 0.216 AC: 2296 AN: 10612

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11224 AN: 67988

Other (OTH) AF: 0.185 AC: 390 AN: 2108

Alfa AF: 0.186 Hom.: 5287

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tatton-Brown-Rahman overgrowth syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.9
DANN	Benign	0.80
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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