Genetic Variant NM_006892.4:c.1572T>C (chr20-32798541-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006892.4(DNMT3B):c.1572T>C(p.Cys524Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,613,938 control chromosomes in the GnomAD database, including 222,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 30448 hom., cov: 34)

Exomes 𝑓: 0.50 ( 191649 hom. )

Consequence

DNMT3B
NM_006892.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.70

Publications

34 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 20-32798541-T-C is Benign according to our data. Variant chr20-32798541-T-C is described in ClinVar as Benign. ClinVar VariationId is 338170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006892.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3B	NM_006892.4	MANE Select	c.1572T>C	p.Cys524Cys	synonymous	Exon 15 of 23	NP_008823.1	Q9UBC3-1
DNMT3B	NM_175850.3		c.1548T>C	p.Cys516Cys	synonymous	Exon 14 of 22	NP_787046.1	Q9UBC3-6
DNMT3B	NM_175848.2		c.1512T>C	p.Cys504Cys	synonymous	Exon 14 of 22	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1572T>C	p.Cys524Cys	synonymous	Exon 15 of 23	ENSP00000328547.2	Q9UBC3-1
DNMT3B	ENST00000201963.3	TSL:1	c.1548T>C	p.Cys516Cys	synonymous	Exon 14 of 22	ENSP00000201963.3	Q9UBC3-6
DNMT3B	ENST00000348286.6	TSL:1	c.1512T>C	p.Cys504Cys	synonymous	Exon 14 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

91304

AN:

152070

Hom.:

30392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.599

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.993

Gnomad SAS

AF:

0.687

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.550

GnomAD2 exomes

AF:

0.583

AC:

146018

AN:

250600

AF XY:

0.568

show subpopulations

Gnomad AFR exome

AF:

0.866

Gnomad AMR exome

AF:

0.730

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.998

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.442

Gnomad OTH exome

AF:

0.520

GnomAD4 exome

AF:

0.496

AC:

724666

AN:

1461750

Hom.:

191649

Cov.:

AF XY:

0.497

AC XY:

361658

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.866

AC:

28986

AN:

33480

American (AMR)

AF:

0.718

AC:

32090

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

13356

AN:

26136

East Asian (EAS)

AF:

0.999

AC:

39643

AN:

39698

South Asian (SAS)

AF:

0.655

AC:

56508

AN:

86252

European-Finnish (FIN)

AF:

0.456

AC:

24356

AN:

53380

Middle Eastern (MID)

AF:

0.460

AC:

2654

AN:

5768

European-Non Finnish (NFE)

AF:

0.445

AC:

494827

AN:

1111944

Other (OTH)

AF:

0.534

AC:

32246

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23391

46782

70173

93564

116955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15398

30796

46194

61592

76990

<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:

0.601

AC:

91420

AN:

152188

Hom.:

30448

Cov.:

AF XY:

0.605

AC XY:

45008

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.857

AC:

35620

AN:

41564

American (AMR)

AF:

0.600

AC:

9175

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1775

AN:

3466

East Asian (EAS)

AF:

0.993

AC:

5135

AN:

5170

South Asian (SAS)

AF:

0.685

AC:

3312

AN:

4832

European-Finnish (FIN)

AF:

0.452

AC:

4786

AN:

10578

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.438

AC:

29798

AN:

67958

Other (OTH)

AF:

0.550

AC:

1164

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1625

3251

4876

6502

8127

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:

0.497

Hom.:

31436

Bravo

AF:

0.624

Asia WGS

AF:

0.842

AC:

2925

AN:

3478

EpiCase

AF:

0.430

EpiControl

AF:

0.426

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (2)

not specified (2)

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=78/22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over