rs6141813

Variant names:

• chr20-32778437-A-G
• rs6141813
• NM_006892.4:c.-6-1881A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006892.4(DNMT3B):​c.-6-1881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 151,758 control chromosomes in the GnomAD database, including 3,822 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3822 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.673
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-6-1881A>G		intron_variant	Intron 1 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.-6-1881A>G		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32622 AN: 151662 Hom.: 3822 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.204

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.215 AC: 32638 AN: 151758 Hom.: 3822 Cov.: 32 AF XY: 0.219 AC XY: 16239 AN XY: 74132

African (AFR) AF: 0.280 AC: 11592 AN: 41346

American (AMR) AF: 0.209 AC: 3188 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 838 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1891 AN: 5116

South Asian (SAS) AF: 0.312 AC: 1494 AN: 4796

European-Finnish (FIN) AF: 0.140 AC: 1473 AN: 10504

Middle Eastern (MID) AF: 0.207 AC: 60 AN: 290

European-Non Finnish (NFE) AF: 0.167 AC: 11377 AN: 67946

Other (OTH) AF: 0.203 AC: 428 AN: 2104

Alfa AF: 0.188 Hom.: 8055

Bravo AF: 0.222

Asia WGS AF: 0.261 AC: 910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.75
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs6141813; hg19: chr20-31366243;