NM_006892.4:c.1252+13T>G

Variant names:

• chr20-32795547-T-G
• rs910085
• NM_006892.4:c.1252+13T>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.1252+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,894 control chromosomes in the GnomAD database, including 156,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15785 hom., cov: 32)
  • Exomes 𝑓: 0.42 (140272 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.65
• Publications: 27 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=-0.91).
• BP6: Variant 20-32795547-T-G is Benign according to our data. Variant chr20-32795547-T-G is described in ClinVar as Benign. ClinVar VariationId is 338165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.1252+13T>G		intron_variant	Intron 11 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1252+13T>G		intron_variant	Intron 11 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66845 AN: 151944 Hom.: 15771 Cov.: 32

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.407

GnomAD2 exomes AF: 0.494 AC: 124207 AN: 251356 AF XY: 0.487

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.676

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.925

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.423 AC: 618817 AN: 1461832 Hom.: 140272 Cov.: 67 AF XY: 0.426 AC XY: 310143 AN XY: 727222

African (AFR) AF: 0.453 AC: 15177 AN: 33480

American (AMR) AF: 0.659 AC: 29481 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11030 AN: 26134

East Asian (EAS) AF: 0.914 AC: 36281 AN: 39700

South Asian (SAS) AF: 0.591 AC: 50980 AN: 86246

European-Finnish (FIN) AF: 0.384 AC: 20507 AN: 53416

Middle Eastern (MID) AF: 0.353 AC: 2038 AN: 5768

European-Non Finnish (NFE) AF: 0.384 AC: 426911 AN: 1111980

Other (OTH) AF: 0.437 AC: 26412 AN: 60390

GnomAD4 genome AF: 0.440 AC: 66892 AN: 152062 Hom.: 15785 Cov.: 32 AF XY: 0.447 AC XY: 33233 AN XY: 74318

African (AFR) AF: 0.456 AC: 18902 AN: 41478

American (AMR) AF: 0.519 AC: 7927 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1446 AN: 3468

East Asian (EAS) AF: 0.921 AC: 4762 AN: 5172

South Asian (SAS) AF: 0.608 AC: 2932 AN: 4824

European-Finnish (FIN) AF: 0.382 AC: 4039 AN: 10580

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25530 AN: 67960

Other (OTH) AF: 0.408 AC: 858 AN: 2104

Alfa AF: 0.383 Hom.: 13994

Bravo AF: 0.452

Asia WGS AF: 0.690 AC: 2396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26851945) -

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

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.91
CADD	Benign	0.35
DANN	Benign	0.53
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs910085; hg19: chr20-31383353;