NM_006892.4:c.1760-8C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006892.4(DNMT3B):c.1760-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,128 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 75 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 74 hom. )

Consequence

DNMT3B
NM_006892.4 splice_region, intron

Scores

Splicing: ADA: 0.0002089

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.14

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency-centromeric instability-facial anomalies syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
facioscapulohumeral muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency-centromeric instability-facial anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNMT3B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-32800145-C-G is Benign according to our data. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-G is described in CliVar as Benign. Clinvar id is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4 link	c.1760-8C>G		splice_region_variant, intron_variant	Intron 16 of 22	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.1760-8C>G		splice_region_variant, intron_variant	Intron 16 of 22	1	NM_006892.4	ENSP00000328547.2		Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2742

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00752

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00483

AC:

1215

AN:

251492

AF XY:

0.00360

show subpopulations

Gnomad AFR exome

AF:

0.0631

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00212

AC:

3093

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1340

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0655

AC:

2194

AN:

33480

American (AMR)

AF:

0.00344

AC:

154

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000185

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000350

AC:

389

AN:

1111998

Other (OTH)

AF:

0.00508

AC:

307

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

167

334

501

668

835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0181

AC:

2759

AN:

152260

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1293

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0622

AC:

2584

AN:

41520

American (AMR)

AF:

0.00751

AC:

115

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68032

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

138

275

413

550

688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.0211

EpiCase

AF:

0.000763

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Benign:1

Jan 12, 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. -

DNMT3B-related disorder

Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Benign:1

Jan 27, 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

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.45

(source)

DANN

Benign

0.47

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.064

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over