Genetic Variant DNMT3B:c.-274C>T (chr20-32762432-C-T) – ACMG Classification: Benign (-20 pts)

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.-274C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 157,506 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 46 hom., cov: 32)

Exomes 𝑓: 0.031 ( 5 hom. )

Consequence

DNMT3B
NM_006892.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.28

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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
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=-0.78).

BP6

Variant 20-32762432-C-T is Benign according to our data. Variant chr20-32762432-C-T is described in ClinVar as Benign. ClinVar VariationId is 338146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0206 (3118/151724) while in subpopulation NFE AF = 0.0303 (2057/67832). AF 95% confidence interval is 0.0292. There are 46 homozygotes in GnomAd4. There are 1462 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 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.-274C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_008823.1	Q9UBC3-1
DNMT3B	NM_006892.4	MANE Select	c.-274C>T	5_prime_UTR	Exon 1 of 23	NP_008823.1	Q9UBC3-1
DNMT3B	NM_175848.2		c.-274C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-274C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000328547.2	Q9UBC3-1
DNMT3B	ENST00000348286.6	TSL:1	c.-274C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000337764.2	Q9UBC3-3
DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-274C>T	5_prime_UTR	Exon 1 of 23	ENSP00000328547.2	Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3118

AN:

151616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00445

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0539

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00827

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0236

GnomAD2 exomes

AF:

0.0124

AC:

AN:

322

AF XY:

0.0106

show subpopulations

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0311

AC:

180

AN:

5782

Hom.:

Cov.:

AF XY:

0.0284

AC XY:

113

AN XY:

3984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

170

South Asian (SAS)

AF:

0.0188

AC:

AN:

584

European-Finnish (FIN)

AF:

0.0978

AC:

AN:

Middle Eastern (MID)

AF:

0.0227

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0321

AC:

146

AN:

4550

Other (OTH)

AF:

0.0337

AC:

AN:

208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0206

AC:

3118

AN:

151724

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1462

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.00443

AC:

184

AN:

41504

American (AMR)

AF:

0.0170

AC:

260

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

187

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0233

AC:

242

AN:

10404

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0303

AC:

2057

AN:

67832

Other (OTH)

AF:

0.0233

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

156

311

467

622

778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0257

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.00690

AC:

AN:

3346

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-1.3

PromoterAI

-0.027

Neutral

(source)

Mutation Taster

=300/0

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