20-32762432-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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=-0.78).
• 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_single_submitter, 1 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 GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	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	c.-274C>T		5_prime_UTR_variant	1/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3118 AN: 151616 Hom.: 46 Cov.: 32

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: 4 AN: 322 Hom.: 0 AF XY: 0.0106 AC XY: 2 AN XY: 188

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.: 5 Cov.: 0 AF XY: 0.0284 AC XY: 113 AN XY: 3984

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.: 46 Cov.: 32 AF XY: 0.0197 AC XY: 1462 AN XY: 74178

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.: 6

Bravo AF: 0.0198

Asia WGS AF: 0.00690 AC: 24 AN: 3346

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 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	11
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

Other links and lift over

dbSNP: rs139762513; hg19: chr20-31350238;