rs147945634

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1

The NM_006892.4(DNMT3B):c.608C>T(p.Pro203Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P203P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

DNMT3B
NM_006892.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.32

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 Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, DNMT3B

BP4

Computational evidence support a benign effect (MetaRNN=0.0051976144).

BP6

Variant 20-32787405-C-T is Benign according to our data. Variant chr20-32787405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00172 (262/152300) while in subpopulation AFR AF= 0.00592 (246/41550). AF 95% confidence interval is 0.00531. There are 0 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4 linkuse as main transcript	c.608C>T	p.Pro203Leu	missense_variant	6/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6 linkuse as main transcript	c.608C>T	p.Pro203Leu	missense_variant	6/23	1	NM_006892.4	A2	Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000518

AC:

130

AN:

251134

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00672

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000211

AC:

309

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00636

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152300

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00592

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.00200

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Apr 06, 2020

DNMT3B NM_006892.3 exon 6 p.Pro203Leu (c.608C>T): This variant has not been reported in the literature but is present in 0.6% (160/24940) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/20-31375211-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:530707). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1;C5561960:Facioscapulohumeral muscular dystrophy 4, digenic

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2020

- -

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

DNMT3B-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;.;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.0052

T;T;T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.76

N;N;N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.015

D;D;D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;D;D;D

Polyphen

0.15

B;B;B;.;.;B

Vest4

0.21

MVP

0.54

MPC

0.23

ClinPred

0.019

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.31

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