20-32779273-G-T

Variant names:

• chr20-32779273-G-T
• rs1569686
• NM_006892.4:c.-6-1045G>T

Variant summary

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

The NM_006892.4(DNMT3B):​c.-6-1045G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 152,124 control chromosomes in the GnomAD database, including 28,220 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 0.57 (28220 hom., cov: 33)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 71 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.-6-1045G>T		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175848.2		c.-6-1045G>T		intron	N/A	NP_787044.1	Q9UBC3-2
	DNMT3B	NM_001424351.1		c.-6-1045G>T		intron	N/A	NP_001411280.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-6-1045G>T		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000348286.6	TSL:1	c.-6-1045G>T		intron	N/A	ENSP00000337764.2	Q9UBC3-3
	DNMT3B	ENST00000353855.6	TSL:5	c.-6-1045G>T		intron	N/A	ENSP00000313397.4	Q9UBC3-2

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86731 AN: 152006 Hom.: 28166 Cov.: 33

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.571 AC: 86843 AN: 152124 Hom.: 28220 Cov.: 33 AF XY: 0.575 AC XY: 42723 AN XY: 74348

African (AFR) AF: 0.858 AC: 35649 AN: 41540

American (AMR) AF: 0.577 AC: 8816 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1543 AN: 3472

East Asian (EAS) AF: 0.923 AC: 4775 AN: 5174

South Asian (SAS) AF: 0.657 AC: 3166 AN: 4818

European-Finnish (FIN) AF: 0.398 AC: 4210 AN: 10572

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.398 AC: 27043 AN: 67956

Other (OTH) AF: 0.515 AC: 1086 AN: 2110

Alfa AF: 0.434 Hom.: 1862

Bravo AF: 0.597

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.38
PhyloP100		0.10
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: rs1569686; hg19: chr20-31367079;