20-32780142-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000201963.3(DNMT3B):c.27C>T(p.Ser9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,566 control chromosomes in the GnomAD database, including 3,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (654 hom., cov: 31)
  • Exomes 𝑓: 0.062 (3159 hom.)
• Consequence: DNMT3B ENST00000201963.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.388

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-32780142-C-T is Benign according to our data. Variant chr20-32780142-C-T is described in ClinVar as [Benign]. Clinvar id is 402792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.-6-176C>T		intron_variant		ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.-6-176C>T		intron_variant		1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12827 AN: 151962 Hom.: 652 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0594

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0654 AC: 16231 AN: 248260 Hom.: 685 AF XY: 0.0637 AC XY: 8590 AN XY: 134832

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0745

Gnomad EAS exome AF: 0.0727

Gnomad SAS exome AF: 0.0662

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0604

Gnomad OTH exome AF: 0.0654

GnomAD4 exome AF: 0.0622 AC: 90953 AN: 1461486 Hom.: 3159 Cov.: 32 AF XY: 0.0617 AC XY: 44842 AN XY: 727032

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0370

Gnomad4 ASJ exome AF: 0.0755

Gnomad4 EAS exome AF: 0.0848

Gnomad4 SAS exome AF: 0.0638

Gnomad4 FIN exome AF: 0.0708

Gnomad4 NFE exome AF: 0.0586

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.0845 AC: 12846 AN: 152080 Hom.: 654 Cov.: 31 AF XY: 0.0847 AC XY: 6294 AN XY: 74326

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.0737

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.0594

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0615 Hom.: 270

Bravo AF: 0.0849

Asia WGS AF: 0.140 AC: 486 AN: 3478

EpiCase AF: 0.0576

EpiControl AF: 0.0541

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	15
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs6058885; hg19: chr20-31367948; COSMIC: COSV52419385;