20-32804560-A-G

Variant names:

• chr20-32804560-A-G
• rs4911110
• NM_006892.4:c.2232-778A>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.2232-778A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,986 control chromosomes in the GnomAD database, including 27,540 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 (27540 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 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.2232-778A>G		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.2208-778A>G		intron	N/A	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.2172-778A>G		intron	N/A	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.2232-778A>G		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.2208-778A>G		intron	N/A	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.2171+2090A>G		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85905 AN: 151868 Hom.: 27485 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.566 AC: 86017 AN: 151986 Hom.: 27540 Cov.: 32 AF XY: 0.570 AC XY: 42283 AN XY: 74242

African (AFR) AF: 0.841 AC: 34894 AN: 41514

American (AMR) AF: 0.574 AC: 8762 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1508 AN: 3464

East Asian (EAS) AF: 0.924 AC: 4774 AN: 5166

South Asian (SAS) AF: 0.654 AC: 3148 AN: 4812

European-Finnish (FIN) AF: 0.399 AC: 4188 AN: 10506

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27112 AN: 67952

Other (OTH) AF: 0.512 AC: 1078 AN: 2106

Alfa AF: 0.475 Hom.: 2786

Bravo AF: 0.592

Asia WGS AF: 0.762 AC: 2649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.54
DANN	Benign	0.43
PhyloP100		-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: rs4911110; hg19: chr20-31392366;