dbSNP rs143448185: DNMT3B:c.1996+9C>T (chr20-32800934-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006892.4(DNMT3B):c.1996+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,164 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

DNMT3B
NM_006892.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.167

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, 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 20-32800934-C-T is Benign according to our data. Variant chr20-32800934-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338183.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00129 (197/152332) while in subpopulation AMR AF = 0.00445 (68/15298). AF 95% confidence interval is 0.0036. There are 1 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
DNMT3B	NM_006892.4	MANE Select	c.1996+9C>T	intron	N/A	NP_008823.1	Q9UBC3-1
DNMT3B	NM_175850.3		c.1972+9C>T	intron	N/A	NP_787046.1	Q9UBC3-6
DNMT3B	NM_175848.2		c.1936+9C>T	intron	N/A	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1996+9C>T	intron	N/A	ENSP00000328547.2	Q9UBC3-1
DNMT3B	ENST00000201963.3	TSL:1	c.1972+9C>T	intron	N/A	ENSP00000201963.3	Q9UBC3-6
DNMT3B	ENST00000348286.6	TSL:1	c.1936+9C>T	intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00123

AC:

309

AN:

251466

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00122

AC:

1782

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

886

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.00221

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00440

AC:

115

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000522

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00123

AC:

1370

AN:

1111974

Other (OTH)

AF:

0.00200

AC:

121

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00129

AC:

197

AN:

152332

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41570

American (AMR)

AF:

0.00445

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68036

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

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:

0.00108

Hom.:

Bravo

AF:

0.00159

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.3

(source)

DANN

Benign

0.62

PhyloP100

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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