20-32800145-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006892.4(DNMT3B):c.1760-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,614,126 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (89 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003183
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-32800145-C-T is Benign according to our data. Variant chr20-32800145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800145-C-T is described in Lovd as [Likely_benign]. Variant chr20-32800145-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.004 (609/152274) while in subpopulation AMR AF= 0.00333 (51/15306). AF 95% confidence interval is 0.00287. There are 11 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.1760-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1760-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152156 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00529 AC: 1330 AN: 251492 Hom.: 40 AF XY: 0.00530 AC XY: 721 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0810

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00394 AC: 5755 AN: 1461852 Hom.: 89 Cov.: 30 AF XY: 0.00409 AC XY: 2974 AN XY: 727230

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0797

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00264

Gnomad4 OTH exome AF: 0.00768

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152274 Hom.: 11 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74452

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.0734

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0105 Hom.: 11

Bravo AF: 0.00447

EpiCase AF: 0.00414

EpiControl AF: 0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DNMT3B: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DNMT3B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	-0.80
Cadd	Benign	0.29
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs2424926; hg19: chr20-31387951;