Variant chr20-32762432-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006892.4(DNMT3B):c.-274C>T variant causes a 5 prime UTR 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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.28

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4 linkuse as main transcript	c.-274C>T		5_prime_UTR_variant	1/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6 linkuse as main transcript	c.-274C>T		5_prime_UTR_variant	1/23	1	NM_006892.4	A2	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

GnomAD3 exomes

AF:

0.0124

AC:

AN:

322

Hom.:

AF XY:

0.0106

AC XY:

AN XY:

188

show subpopulations

Gnomad SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0188

Gnomad4 FIN exome

AF:

0.0978

Gnomad4 NFE exome

AF:

0.0321

Gnomad4 OTH exome

AF:

0.0337

GnomAD4 genome

AF:

0.0206

AC:

3118

AN:

151724

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1462

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00443

Gnomad4 AMR

AF:

0.0170

Gnomad4 ASJ

AF:

0.0539

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00828

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.0303

Gnomad4 OTH

AF:

0.0233

Alfa

AF:

0.0257

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.00690

AC:

AN:

3346

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over