2-25300227-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022552.5(DNMT3A):c.89A>C(p.Glu30Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00274 in 1,608,508 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E30G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0027 ( 11 hom. )

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 4.37

Publications

22 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073841214).

BP6

Variant 2-25300227-T-G is Benign according to our data. Variant chr2-25300227-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 133982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00326 (496/152264) while in subpopulation NFE AF = 0.00291 (198/68012). AF 95% confidence interval is 0.00258. There are 8 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 496 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5 link	c.89A>C	p.Glu30Ala	missense_variant	Exon 3 of 23	ENST00000321117.10	NP_072046.2	Q9Y6K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNMT3A	ENST00000321117.10 link	c.89A>C	p.Glu30Ala	missense_variant	Exon 3 of 23	1	NM_022552.5	ENSP00000324375.5	Q9Y6K1-1
DNMT3A	ENST00000264709.7 link	c.89A>C	p.Glu30Ala	missense_variant	Exon 3 of 23	1		ENSP00000264709.3	Q9Y6K1-1
DNMT3A	ENST00000406659.3 link	c.89A>C	p.Glu30Ala	missense_variant	Exon 3 of 4	1		ENSP00000384852.3	Q9Y6K1-3
DNMT3A	ENST00000380756.7 link	n.89A>C		non_coding_transcript_exon_variant	Exon 3 of 24	1		ENSP00000370132.3	F8WE91

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

496

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00326

AC:

801

AN:

245602

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00361

GnomAD4 exome

AF:

0.00269

AC:

3912

AN:

1456244

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1879

AN XY:

724710

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33472

American (AMR)

AF:

0.00165

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000371

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0187

AC:

895

AN:

47934

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00241

AC:

2681

AN:

1111934

Other (OTH)

AF:

0.00250

AC:

151

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

210

420

629

839

1049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00326

AC:

496

AN:

152264

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41554

American (AMR)

AF:

0.00157

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0215

AC:

228

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00291

AC:

198

AN:

68012

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00239

Hom.:

Bravo

AF:

0.00161

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00292

AC:

354

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNMT3A: BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21519343, 32199932) -

Apr 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tatton-Brown-Rahman overgrowth syndrome

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNMT3A-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

.;T;T

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

0.69

N;N;N

PhyloP100

4.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.24

N;N;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.063

T;T;T

Polyphen

0.88

P;P;D

Vest4

0.39

MVP

0.99

MPC

1.3

ClinPred

0.038

GERP RS

5.3

Varity_R

0.14

gMVP

0.14

Mutation Taster

=91/9

polymorphism

(source)

Splicing

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

Publications

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2-25300227-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over