2-25300227-T-G

Position:

chr2-25300227-T-G

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

DNMT3A (HGNC:):

DNMT3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr2-25300227-T-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 496 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3A	NM_022552.5 linkuse as main transcript	c.89A>C	p.Glu30Ala	missense_variant	3/23	ENST00000321117.10	NP_072046.2	Q9Y6K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNMT3A	ENST00000321117.10 linkuse as main transcript	c.89A>C	p.Glu30Ala	missense_variant	3/23	1	NM_022552.5	ENSP00000324375.5	Q9Y6K1-1
DNMT3A	ENST00000264709.7 linkuse as main transcript	c.89A>C	p.Glu30Ala	missense_variant	3/23	1		ENSP00000264709.3	Q9Y6K1-1
DNMT3A	ENST00000406659.3 linkuse as main transcript	c.89A>C	p.Glu30Ala	missense_variant	3/4	1		ENSP00000384852.3	Q9Y6K1-3
DNMT3A	ENST00000380756.7 linkuse as main transcript	n.89A>C		non_coding_transcript_exon_variant	3/24	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

GnomAD3 exomes

AF:

0.00326

AC:

801

AN:

245602

Hom.:

AF XY:

0.00328

AC XY:

437

AN XY:

133338

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 SAS exome

AF:

0.000262

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

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.00241

Gnomad4 OTH exome

AF:

0.00250

GnomAD4 genome

AF:

0.00326

AC:

496

AN:

152264

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0215

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00219

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	This variant is associated with the following publications: (PMID: 21519343, 32199932) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DNMT3A: BS2 -

Tatton-Brown-Rahman overgrowth syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

DNMT3A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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

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

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over