Genetic Variant NM_175867.3:c.832A>G (chr21-44250887-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175867.3(DNMT3L):c.832A>G(p.Arg278Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 0)

Consequence

DNMT3L
NM_175867.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

Publications

48 publications found

Variant links:

Genes affected

DNMT3L (HGNC:2980): (DNA methyltransferase 3 like) 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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

DNMT3L links:

DNMT3L-AS1 (HGNC:40189): (DNMT3L antisense RNA 1)

DNMT3L-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009047687).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175867.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNMT3L	NM_175867.3	MANE Select	c.832A>G	p.Arg278Gly	missense	Exon 10 of 12	NP_787063.1
DNMT3L	NM_013369.4		c.832A>G	p.Arg278Gly	missense	Exon 10 of 12	NP_037501.2
DNMT3L-AS1	NR_135514.1		n.75T>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.832A>G	p.Arg278Gly	missense	Exon 10 of 12	ENSP00000486001.1
DNMT3L	ENST00000270172.7	TSL:1	c.832A>G	p.Arg278Gly	missense	Exon 10 of 12	ENSP00000270172.3
DNMT3L	ENST00000431166.1	TSL:5	c.787A>G	p.Arg263Gly	missense	Exon 9 of 9	ENSP00000400242.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.210

AC:

52546

AN:

249668

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.0459

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.255

Hom.:

22332

TwinsUK

AF:

0.260

AC:

963

ALSPAC

AF:

0.273

AC:

1053

ESP6500AA

AF:

0.239

AC:

1051

ESP6500EA

AF:

0.263

AC:

2265

ExAC

AF:

0.214

AC:

25983

Asia WGS

AF:

0.115

AC:

401

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Uncertain

0.76

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.6

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-6.1

REVEL

Benign

0.13

Sift

Uncertain

0.025

Sift4G

Uncertain

0.0020

Polyphen

0.52

Vest4

0.13

MPC

0.36

ClinPred

0.037

GERP RS

0.12

Varity_R

0.47

gMVP

0.61

Mutation Taster

=99/1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over