20-32800145-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006892.4(DNMT3B):c.1760-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,614,126 control chromosomes in the GnomAD database, including 100 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 89 hom. )

Consequence

DNMT3B
NM_006892.4 splice_region, intron

Scores

Splicing: ADA: 0.00003183

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

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=-0.8).

BP6

Variant 20-32800145-C-T is Benign according to our data. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.004 (609/152274) while in subpopulation AMR AF = 0.00333 (51/15306). AF 95% confidence interval is 0.00287. There are 11 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.0734

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00529

AC:

1330

AN:

251492

AF XY:

0.00530

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.0810

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00334

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.00394

AC:

5755

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

2974

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0797

AC:

2082

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00131

AC:

113

AN:

86256

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00264

AC:

2939

AN:

1111988

Other (OTH)

AF:

0.00768

AC:

464

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

321

642

962

1283

1604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00400

AC:

609

AN:

152274

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41534

American (AMR)

AF:

0.00333

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0734

AC:

255

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68032

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0105

Hom.:

Bravo

AF:

0.00447

EpiCase

AF:

0.00414

EpiControl

AF:

0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNMT3B: BP4, BS2 -

Jan 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DNMT3B-related disorder

Benign:1

Jul 03, 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

Feb 03, 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

-0.80

CADD

Benign

0.29

(source)

DANN

Benign

0.46

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0020

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