chr20-32800148-C-G

Variant names:

• chr20-32800148-C-G
• rs1997797
• NM_006892.4:c.1760-5C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006892.4(DNMT3B):​c.1760-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,836 control chromosomes in the GnomAD database, including 212,830 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25798 hom., cov: 33)
  • Exomes 𝑓: 0.49 (187032 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005282
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -2.28
• Publications: 22 publications found

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]

DNMT3B Gene-Disease associations (from GenCC):

• immunodeficiency-centromeric instability-facial anomalies syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facioscapulohumeral muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency-centromeric instability-facial anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-32800148-C-G is Benign according to our data. Variant chr20-32800148-C-G is described in ClinVar as Benign. ClinVar VariationId is 338175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.1760-5C>G		splice_region_variant, intron_variant	Intron 16 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1760-5C>G		splice_region_variant, intron_variant	Intron 16 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85326 AN: 152010 Hom.: 25767 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.571 AC: 143672 AN: 251480 AF XY: 0.560

Gnomad AFR exome AF: 0.728

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.491 AC: 718266 AN: 1461708 Hom.: 187032 Cov.: 61 AF XY: 0.494 AC XY: 358865 AN XY: 727164

African (AFR) AF: 0.730 AC: 24451 AN: 33480

American (AMR) AF: 0.709 AC: 31702 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13305 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39640 AN: 39696

South Asian (SAS) AF: 0.655 AC: 56451 AN: 86246

European-Finnish (FIN) AF: 0.455 AC: 24300 AN: 53414

Middle Eastern (MID) AF: 0.449 AC: 2587 AN: 5760

European-Non Finnish (NFE) AF: 0.444 AC: 494187 AN: 1111870

Other (OTH) AF: 0.524 AC: 31643 AN: 60386

GnomAD4 genome AF: 0.561 AC: 85414 AN: 152128 Hom.: 25798 Cov.: 33 AF XY: 0.567 AC XY: 42125 AN XY: 74360

African (AFR) AF: 0.724 AC: 30037 AN: 41506

American (AMR) AF: 0.582 AC: 8897 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1766 AN: 3466

East Asian (EAS) AF: 0.993 AC: 5149 AN: 5184

South Asian (SAS) AF: 0.686 AC: 3306 AN: 4822

European-Finnish (FIN) AF: 0.451 AC: 4764 AN: 10560

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29749 AN: 67986

Other (OTH) AF: 0.520 AC: 1093 AN: 2102

Alfa AF: 0.477 Hom.: 5894

Bravo AF: 0.580

Asia WGS AF: 0.830 AC: 2885 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.42
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.056
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

Other links and lift over

dbSNP: rs1997797; hg19: chr20-31387954;