rs2424932

Variant names:

• chr20-32808730-A-G
• rs2424932
• NM_006892.4:c.*827A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-32808730-A-G
• chr20-32808730-A-T

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.*827A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 228,750 control chromosomes in the GnomAD database, including 57,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39691 hom., cov: 30)
  • Exomes 𝑓: 0.66 (17523 hom.)
• Consequence: DNMT3B NM_006892.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 47 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 20-32808730-A-G is Benign according to our data. Variant chr20-32808730-A-G is described in ClinVar as Benign. ClinVar VariationId is 338197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.*827A>G		3_prime_UTR_variant	Exon 23 of 23	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.*827A>G		3_prime_UTR_variant	Exon 23 of 23	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108001 AN: 151790 Hom.: 39642 Cov.: 30

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.686

GnomAD4 exome AF: 0.664 AC: 51051 AN: 76842 Hom.: 17523 Cov.: 0 AF XY: 0.658 AC XY: 23387 AN XY: 35534

African (AFR) AF: 0.885 AC: 3252 AN: 3674

American (AMR) AF: 0.744 AC: 1740 AN: 2338

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 3013 AN: 4880

East Asian (EAS) AF: 0.905 AC: 9848 AN: 10880

South Asian (SAS) AF: 0.766 AC: 515 AN: 672

European-Finnish (FIN) AF: 0.625 AC: 50 AN: 80

Middle Eastern (MID) AF: 0.584 AC: 278 AN: 476

European-Non Finnish (NFE) AF: 0.593 AC: 28134 AN: 47446

Other (OTH) AF: 0.660 AC: 4221 AN: 6396

GnomAD4 genome AF: 0.712 AC: 108107 AN: 151908 Hom.: 39691 Cov.: 30 AF XY: 0.716 AC XY: 53161 AN XY: 74224

African (AFR) AF: 0.883 AC: 36605 AN: 41456

American (AMR) AF: 0.724 AC: 11039 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2136 AN: 3472

East Asian (EAS) AF: 0.926 AC: 4774 AN: 5158

South Asian (SAS) AF: 0.756 AC: 3632 AN: 4806

European-Finnish (FIN) AF: 0.644 AC: 6787 AN: 10532

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40865 AN: 67924

Other (OTH) AF: 0.683 AC: 1441 AN: 2110

Alfa AF: 0.643 Hom.: 110048

Bravo AF: 0.726

Asia WGS AF: 0.812 AC: 2821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.35
DANN	Benign	0.51
PhyloP100		-1.5
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: rs2424932; hg19: chr20-31396536;