Variant 2-25234352-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_022552.5(DNMT3A):c.2666T>G(p.Leu889Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain SAM-dependent MTase C5-type (size 278) in uniprot entity DNM3A_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_022552.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5 link	c.2666T>G	p.Leu889Arg	missense_variant	Exon 23 of 23	ENST00000321117.10	NP_072046.2	Q9Y6K1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10 link	c.2666T>G	p.Leu889Arg	missense_variant	Exon 23 of 23	1	NM_022552.5	ENSP00000324375.5		Q9Y6K1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727202

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Uncertain:1

Mar 13, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This DNMT3A variant is absent from a large population dataset and has not been reported in ClinVar or the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging, and the leucine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 23 splicing, although this has not been confirmed experimentally to our knowledge. This amino acid substitution occurs in the methyltransferase (MTase) catalytic domain of the DNMT3A protein. Due to insufficient evidence, we consider the clinical significance of c.2666T>G (p.Leu889Arg) to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D;T

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.7

D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.96

MutPred

0.91

Gain of methylation at L889 (P = 0.0071);.;Gain of methylation at L889 (P = 0.0071);.;

MVP

0.96

MPC

1.5

ClinPred

1.0

GERP RS

5.8

Varity_R

0.96

gMVP

0.96

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over