Genetic Variant NM_022552.5:c.1266G>A (chr2-25246633-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.673

Publications

31 publications found

Variant links:

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)

DNMT3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNMT3A	NM_022552.5	MANE Select	c.1266G>A	p.Leu422Leu	synonymous	Exon 10 of 23	NP_072046.2
DNMT3A	NM_175629.2		c.1266G>A	p.Leu422Leu	synonymous	Exon 10 of 23	NP_783328.1
DNMT3A	NM_001320893.1		c.810G>A	p.Leu270Leu	synonymous	Exon 5 of 18	NP_001307822.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.1266G>A	p.Leu422Leu	synonymous	Exon 10 of 23	ENSP00000324375.5
DNMT3A	ENST00000264709.7	TSL:1	c.1266G>A	p.Leu422Leu	synonymous	Exon 10 of 23	ENSP00000264709.3
DNMT3A	ENST00000380746.8	TSL:1	c.699G>A	p.Leu233Leu	synonymous	Exon 6 of 19	ENSP00000370122.4

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31799

AN:

152058

Hom.:

3622

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.166

AC XY:

120277

AN XY:

726354

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

11927

23854

35780

47707

59634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6448

12896

19344

25792

32240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.209

AC:

31839

AN:

152178

Hom.:

3635

Cov.:

AF XY:

0.211

AC XY:

15714

AN XY:

74420

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11224

AN:

67988

Other (OTH)

AF:

0.185

AC:

390

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1296

2592

3888

5184

6480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

6.9

(source)

DANN

Benign

0.80

PhyloP100

0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over