20-32800931-C-T

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.1996+6C>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 0.00362 in 1,614,140 control chromosomes in the GnomAD database, including 148 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 ( 74 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 74 hom. )

Consequence

DNMT3B
NM_006892.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0002216
2

Clinical Significance

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

Conservation

PhyloP100: -0.0280

Publications

1 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

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=-0.71).
BP6
Variant 20-32800931-C-T is Benign according to our data. Variant chr20-32800931-C-T is described in ClinVar as [Benign]. Clinvar id is 338181.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
DNMT3BNM_006892.4 linkc.1996+6C>T splice_region_variant, intron_variant Intron 18 of 22 ENST00000328111.6 NP_008823.1 Q9UBC3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNMT3BENST00000328111.6 linkc.1996+6C>T splice_region_variant, intron_variant Intron 18 of 22 1 NM_006892.4 ENSP00000328547.2 Q9UBC3-1

Frequencies

GnomAD3 genomes
AF:
0.0180
AC:
2744
AN:
152220
Hom.:
73
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0620
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00753
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:
1214
AN:
251476
AF XY:
0.00359
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:
0.00211
AC:
3086
AN:
1461802
Hom.:
74
Cov.:
35
AF XY:
0.00184
AC XY:
1336
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.0654
AC:
2190
AN:
33474
American (AMR)
AF:
0.00342
AC:
153
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.000185
AC:
16
AN:
86254
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53404
Middle Eastern (MID)
AF:
0.00555
AC:
32
AN:
5768
European-Non Finnish (NFE)
AF:
0.000350
AC:
389
AN:
1111956
Other (OTH)
AF:
0.00505
AC:
305
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.449
Heterozygous variant carriers
0
169
337
506
674
843
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
80
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:
2761
AN:
152338
Hom.:
74
Cov.:
33
AF XY:
0.0173
AC XY:
1292
AN XY:
74506
show subpopulations
African (AFR)
AF:
0.0622
AC:
2586
AN:
41568
American (AMR)
AF:
0.00752
AC:
115
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.000470
AC:
32
AN:
68032
Other (OTH)
AF:
0.0114
AC:
24
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
129
257
386
514
643
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
32
64
96
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:
0.00597
Hom.:
13
Bravo
AF:
0.0210
Asia WGS
AF:
0.00722
AC:
25
AN:
3478
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
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Sep 11, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
-0.71
CADD
Benign
13
DANN
Benign
0.69
PhyloP100
-0.028
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=98/2
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00022
dbscSNV1_RF
Benign
0.024
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

Other links and lift over

dbSNP: rs77355896; hg19: chr20-31388737; API