Genetic Variant NM_006892.4:c.1491-452C>T (chr20-32798008-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006892.4(DNMT3B):c.1491-452C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 151,806 control chromosomes in the GnomAD database, including 30,337 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 30337 hom., cov: 30)

Consequence

DNMT3B
NM_006892.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.668

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4 link	c.1491-452C>T		intron_variant	Intron 14 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.1491-452C>T		intron_variant	Intron 14 of 22	1	NM_006892.4	ENSP00000328547.2		Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

91037

AN:

151688

Hom.:

30282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.993

Gnomad SAS

AF:

0.690

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.550

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.600

AC:

91152

AN:

151806

Hom.:

30337

Cov.:

AF XY:

0.605

AC XY:

44868

AN XY:

74162

show subpopulations

African (AFR)

AF:

0.857

AC:

35480

AN:

41414

American (AMR)

AF:

0.601

AC:

9162

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1778

AN:

3470

East Asian (EAS)

AF:

0.993

AC:

5115

AN:

5150

South Asian (SAS)

AF:

0.689

AC:

3310

AN:

4804

European-Finnish (FIN)

AF:

0.452

AC:

4759

AN:

10526

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.438

AC:

29737

AN:

67888

Other (OTH)

AF:

0.550

AC:

1158

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1559

3118

4678

6237

7796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

728

1456

2184

2912

3640

<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:

0.505

Hom.:

56952

Bravo

AF:

0.624

Asia WGS

AF:

0.842

AC:

2925

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.8

(source)

DANN

Benign

0.17

PhyloP100

-0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over