Variant rs762537914 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_006892.4(DNMT3B):c.1834G>A(p.Ala612Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNMT3B
NM_006892.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.74

Variant links:

Genes affected

DNMT3B (HGNC:2979): (DNA methyltransferase 3 beta) 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 which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined. [provided by RefSeq, May 2011]

DNMT3B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain SAM-dependent MTase C5-type (size 278) in uniprot entity DNM3B_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_006892.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT3B. . Gene score misZ 1.5 (greater than the threshold 3.09). Trascript score misZ 3.3234 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.09891105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3B	NM_006892.4 linkuse as main transcript	c.1834G>A	p.Ala612Thr	missense_variant	17/23	ENST00000328111.6	NP_008823.1	Q9UBC3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6 linkuse as main transcript	c.1834G>A	p.Ala612Thr	missense_variant	17/23	1	NM_006892.4	ENSP00000328547.2		Q9UBC3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251496

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Uncertain

0.46

T;.;.;.;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.72

T;T;D;D;D;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.099

T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.87

L;.;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.35

N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.66

T;T;T;T;T;T

Sift4G

Benign

0.85

T;T;T;T;T;T

Polyphen

0.12

B;B;B;.;.;B

Vest4

0.13

MutPred

0.28

Gain of methylation at K617 (P = 0.0648);.;.;.;.;.;

MVP

0.63

MPC

1.8

ClinPred

0.73

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.73

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over