rs2424932

chr20-32808730-A-Gchr20-32808730-A-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.*827A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 228,750 control chromosomes in the GnomAD database, including 57,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.71 (39691 hom., cov: 30)
  • Exomes 𝑓: 0.66 (17523 hom.)
• Consequence: DNMT3B NM_006892.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45

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=-0.84).
• BP6: Variant 20-32808730-A-G is Benign according to our data. Variant chr20-32808730-A-G is described in ClinVar as [Benign]. Clinvar id is 338197.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-32808730-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.*827A>G		3_prime_UTR_variant	23/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.*827A>G		3_prime_UTR_variant	23/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108001 AN: 151790 Hom.: 39642 Cov.: 30

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.686

GnomAD4 exome AF: 0.664 AC: 51051 AN: 76842 Hom.: 17523 Cov.: 0 AF XY: 0.658 AC XY: 23387 AN XY: 35534

Gnomad4 AFR exome AF: 0.885

Gnomad4 AMR exome AF: 0.744

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.905

Gnomad4 SAS exome AF: 0.766

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.593

Gnomad4 OTH exome AF: 0.660

GnomAD4 genome AF: 0.712 AC: 108107 AN: 151908 Hom.: 39691 Cov.: 30 AF XY: 0.716 AC XY: 53161 AN XY: 74224

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.724

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.926

Gnomad4 SAS AF: 0.756

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.683

Alfa AF: 0.625 Hom.: 43298

Bravo AF: 0.726

Asia WGS AF: 0.812 AC: 2821 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	-0.84
Cadd	Benign	0.35
Dann	Benign	0.51

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: rs2424932; hg19: chr20-31396536;