rs6058896

Positions:

• chr20-32808346-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006892.4(DNMT3B):​c.*443C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 309,662 control chromosomes in the GnomAD database, including 881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (519 hom., cov: 31)
  • Exomes 𝑓: 0.065 (362 hom.)
• Consequence: DNMT3B NM_006892.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.778

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-32808346-C-T is Benign according to our data. Variant chr20-32808346-C-T is described in ClinVar as [Benign]. Clinvar id is 338192.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.*443C>T		3_prime_UTR_variant	23/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.*443C>T		3_prime_UTR_variant	23/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11662 AN: 151782 Hom.: 514 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0421

Gnomad ASJ AF: 0.0802

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0676

GnomAD4 exome AF: 0.0648 AC: 10227 AN: 157760 Hom.: 362 Cov.: 0 AF XY: 0.0640 AC XY: 4915 AN XY: 76840

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0399

Gnomad4 ASJ exome AF: 0.0691

Gnomad4 EAS exome AF: 0.0886

Gnomad4 SAS exome AF: 0.0593

Gnomad4 FIN exome AF: 0.0657

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0685

GnomAD4 genome AF: 0.0770 AC: 11694 AN: 151902 Hom.: 519 Cov.: 31 AF XY: 0.0768 AC XY: 5702 AN XY: 74256

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.0802

Gnomad4 EAS AF: 0.0707

Gnomad4 SAS AF: 0.0771

Gnomad4 FIN AF: 0.0687

Gnomad4 NFE AF: 0.0591

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0726 Hom.: 106

Bravo AF: 0.0768

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.79
CADD	Benign	4.9
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs6058896; hg19: chr20-31396152;