rs150682895

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_006892.4(DNMT3B):c.1150G>A(p.Ala384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,144 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

DNMT3B
NM_006892.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.217

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the DNMT3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 33 curated benign missense variants. Gene score misZ: 1.5 (below the threshold of 3.09). Trascript score misZ: 3.3234 (above the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023308396).

BP6

Variant 20-32795432-G-A is Benign according to our data. Variant chr20-32795432-G-A is described in ClinVar as [Benign]. Clinvar id is 461480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32795432-G-A is described in Lovd as [Likely_benign]. Variant chr20-32795432-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00952 (1449/152278) while in subpopulation AMR AF= 0.0169 (259/15294). AF 95% confidence interval is 0.0152. There are 6 homozygotes in gnomad4. There are 809 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4 link	c.1150G>A	p.Ala384Thr	missense_variant	Exon 11 of 23	ENST00000328111.6	NP_008823.1	Q9UBC3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6 link	c.1150G>A	p.Ala384Thr	missense_variant	Exon 11 of 23	1	NM_006892.4	ENSP00000328547.2		Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.00953

AC:

1450

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00903

AC:

2271

AN:

251404

Hom.:

AF XY:

0.00926

AC XY:

1258

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00934

Gnomad ASJ exome

AF:

0.00982

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00346

Gnomad FIN exome

AF:

0.0131

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0106

AC:

15503

AN:

1461866

Hom.:

109

Cov.:

AF XY:

0.0105

AC XY:

7665

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00930

Gnomad4 ASJ exome

AF:

0.00869

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00952

AC:

1449

AN:

152278

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

809

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.0169

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0155

Gnomad4 NFE

AF:

0.0126

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00896

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00792

AC:

962

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNMT3B: BP4, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.045

T;.;.;.;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.82

T;T;T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-0.46

N;.;.;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.86

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.88

T;T;T;T;T;T

Sift4G

Benign

0.69

T;T;T;T;T;T

Polyphen

0.0

B;B;B;.;.;B

Vest4

0.14

MVP

0.28

MPC

0.17

ClinPred

0.0054

GERP RS

2.7

Varity_R

0.026

gMVP

0.20

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over