NM_006892.4:c.1906-5T>C

Variant names:

• chr20-32800830-T-C
• rs2424928
• NM_006892.4:c.1906-5T>C

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.1906-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,611,274 control chromosomes in the GnomAD database, including 216,817 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 0.59 (28489 hom., cov: 32)
  • Exomes 𝑓: 0.49 (188328 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009714
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -2.06
• Publications: 26 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=-0.84).
• BP6: Variant 20-32800830-T-C is Benign according to our data. Variant chr20-32800830-T-C is described in ClinVar as Benign. ClinVar VariationId is 338180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.1906-5T>C		splice_region_variant, intron_variant	Intron 17 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1906-5T>C		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88874 AN: 151954 Hom.: 28440 Cov.: 32

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.577 AC: 145181 AN: 251450 AF XY: 0.565

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.493 AC: 719436 AN: 1459200 Hom.: 188328 Cov.: 41 AF XY: 0.495 AC XY: 359341 AN XY: 726062

African (AFR) AF: 0.814 AC: 27144 AN: 33354

American (AMR) AF: 0.713 AC: 31861 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13284 AN: 26118

East Asian (EAS) AF: 0.998 AC: 39558 AN: 39642

South Asian (SAS) AF: 0.654 AC: 56379 AN: 86164

European-Finnish (FIN) AF: 0.455 AC: 24273 AN: 53386

Middle Eastern (MID) AF: 0.454 AC: 2619 AN: 5764

European-Non Finnish (NFE) AF: 0.444 AC: 492423 AN: 1109786

Other (OTH) AF: 0.529 AC: 31895 AN: 60284

GnomAD4 genome AF: 0.585 AC: 88988 AN: 152074 Hom.: 28489 Cov.: 32 AF XY: 0.590 AC XY: 43841 AN XY: 74330

African (AFR) AF: 0.806 AC: 33417 AN: 41476

American (AMR) AF: 0.590 AC: 9021 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1768 AN: 3472

East Asian (EAS) AF: 0.993 AC: 5136 AN: 5172

South Asian (SAS) AF: 0.686 AC: 3310 AN: 4828

European-Finnish (FIN) AF: 0.452 AC: 4770 AN: 10562

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29780 AN: 67974

Other (OTH) AF: 0.537 AC: 1131 AN: 2108

Alfa AF: 0.496 Hom.: 23435

Bravo AF: 0.607

Asia WGS AF: 0.838 AC: 2912 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 12, 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 provided Benign:1 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

- -

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	-0.84
CADD	Benign	9.1
DANN	Benign	0.56
PhyloP100		-2.1
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	0.000097
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs2424928; hg19: chr20-31388636;