rs17123657

Positions:

• chr20-32800274-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006892.4(DNMT3B):​c.1881C>T​(p.Asp627=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,076 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (662 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (692 hom.)
• Consequence: DNMT3B NM_006892.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.532

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 -16 ACMG points.

• BP6: Variant 20-32800274-C-T is Benign according to our data. Variant chr20-32800274-C-T is described in ClinVar as [Benign]. Clinvar id is 338179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.1881C>T	p.Asp627=	synonymous_variant	17/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1881C>T	p.Asp627=	synonymous_variant	17/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8203 AN: 152072 Hom.: 660 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.0579

GnomAD3 exomes AF: 0.0162 AC: 4067 AN: 251494 Hom.: 277 AF XY: 0.0126 AC XY: 1710 AN XY: 135922

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.00757 AC: 11064 AN: 1461884 Hom.: 692 Cov.: 35 AF XY: 0.00691 AC XY: 5027 AN XY: 727246

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0540 AC: 8223 AN: 152192 Hom.: 662 Cov.: 32 AF XY: 0.0524 AC XY: 3901 AN XY: 74404

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0312 Hom.: 190

Bravo AF: 0.0622

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17123657; hg19: chr20-31388080; COSMIC: COSV52414516;