Genetic Variant NM_022552.5:c.2729C>G (chr2-25234289-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_022552.5(DNMT3A):c.2729C>G(p.Ala910Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A910V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DNMT3A
NM_022552.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

Publications

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

DNMT3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_022552.5

PM2

Very rare variant in population databases, with high coverage;

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	UniProt
DNMT3A	NM_022552.5	MANE Select	c.2729C>G	p.Ala910Gly	missense	Exon 23 of 23	NP_072046.2
DNMT3A	NM_175629.2		c.2729C>G	p.Ala910Gly	missense	Exon 23 of 23	NP_783328.1	Q9Y6K1-1
DNMT3A	NM_001320893.1		c.2273C>G	p.Ala758Gly	missense	Exon 18 of 18	NP_001307822.1	Q9Y6K1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.2729C>G	p.Ala910Gly	missense	Exon 23 of 23	ENSP00000324375.5	Q9Y6K1-1
DNMT3A	ENST00000264709.7	TSL:1	c.2729C>G	p.Ala910Gly	missense	Exon 23 of 23	ENSP00000264709.3	Q9Y6K1-1
DNMT3A	ENST00000380746.8	TSL:1	c.2162C>G	p.Ala721Gly	missense	Exon 19 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.57

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

PhyloP100

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.018

Polyphen

0.99

Vest4

0.51

MutPred

0.26

Loss of stability (P = 0.0297)

MVP

0.72

MPC

1.1

ClinPred

0.97

GERP RS

5.5

Varity_R

0.70

gMVP

0.32

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over