20-32798541-T-C

Variant names:

• chr20-32798541-T-C
• rs6058891
• NM_006892.4:c.1572T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006892.4(DNMT3B):​c.1572T>C​(p.Cys524Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,613,938 control chromosomes in the GnomAD database, including 222,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (30448 hom., cov: 34)
  • Exomes 𝑓: 0.50 (191649 hom.)
• Consequence: DNMT3B NM_006892.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.70
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 20-32798541-T-C is Benign according to our data. Variant chr20-32798541-T-C is described in ClinVar as Benign. ClinVar VariationId is 338170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006892.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.1572T>C	p.Cys524Cys	synonymous	Exon 15 of 23	NP_008823.1
	DNMT3B	NM_175850.3		c.1548T>C	p.Cys516Cys	synonymous	Exon 14 of 22	NP_787046.1
	DNMT3B	NM_175848.2		c.1512T>C	p.Cys504Cys	synonymous	Exon 14 of 22	NP_787044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1572T>C	p.Cys524Cys	synonymous	Exon 15 of 23	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.1548T>C	p.Cys516Cys	synonymous	Exon 14 of 22	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.1512T>C	p.Cys504Cys	synonymous	Exon 14 of 20	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91304 AN: 152070 Hom.: 30392 Cov.: 34

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.583 AC: 146018 AN: 250600 AF XY: 0.568

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.730

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.496 AC: 724666 AN: 1461750 Hom.: 191649 Cov.: 75 AF XY: 0.497 AC XY: 361658 AN XY: 727182

African (AFR) AF: 0.866 AC: 28986 AN: 33480

American (AMR) AF: 0.718 AC: 32090 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13356 AN: 26136

East Asian (EAS) AF: 0.999 AC: 39643 AN: 39698

South Asian (SAS) AF: 0.655 AC: 56508 AN: 86252

European-Finnish (FIN) AF: 0.456 AC: 24356 AN: 53380

Middle Eastern (MID) AF: 0.460 AC: 2654 AN: 5768

European-Non Finnish (NFE) AF: 0.445 AC: 494827 AN: 1111944

Other (OTH) AF: 0.534 AC: 32246 AN: 60392

GnomAD4 genome AF: 0.601 AC: 91420 AN: 152188 Hom.: 30448 Cov.: 34 AF XY: 0.605 AC XY: 45008 AN XY: 74396

African (AFR) AF: 0.857 AC: 35620 AN: 41564

American (AMR) AF: 0.600 AC: 9175 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1775 AN: 3466

East Asian (EAS) AF: 0.993 AC: 5135 AN: 5170

South Asian (SAS) AF: 0.685 AC: 3312 AN: 4832

European-Finnish (FIN) AF: 0.452 AC: 4786 AN: 10578

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

European-Non Finnish (NFE) AF: 0.438 AC: 29798 AN: 67958

Other (OTH) AF: 0.550 AC: 1164 AN: 2116

Alfa AF: 0.497 Hom.: 31436

Bravo AF: 0.624

Asia WGS AF: 0.842 AC: 2925 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.426

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

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 provided Benign:1 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.68
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	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: rs6058891; hg19: chr20-31386347; COSMIC: COSV52421449;