20-32787185-G-A

Variant names:

• chr20-32787185-G-A
• rs4911107
• NM_006892.4:c.433-45G>A

Variant summary

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

The NM_006892.4(DNMT3B):​c.433-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,612,584 control chromosomes in the GnomAD database, including 170,719 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 0.47 (17645 hom., cov: 33)
  • Exomes 𝑓: 0.44 (153074 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 25 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=-0.91).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.433-45G>A		intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.469-45G>A		intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.433-45G>A		intron	N/A	NP_787044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.433-45G>A		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.469-45G>A		intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.433-45G>A		intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70970 AN: 151994 Hom.: 17625 Cov.: 33

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.425

GnomAD2 exomes AF: 0.516 AC: 128580 AN: 249018 AF XY: 0.509

Gnomad AFR exome AF: 0.507

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.926

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.444 AC: 648472 AN: 1460472 Hom.: 153074 Cov.: 34 AF XY: 0.447 AC XY: 325059 AN XY: 726640

African (AFR) AF: 0.507 AC: 16959 AN: 33466

American (AMR) AF: 0.667 AC: 29844 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 11099 AN: 26130

East Asian (EAS) AF: 0.912 AC: 36189 AN: 39692

South Asian (SAS) AF: 0.631 AC: 54380 AN: 86188

European-Finnish (FIN) AF: 0.400 AC: 21328 AN: 53264

Middle Eastern (MID) AF: 0.358 AC: 2062 AN: 5752

European-Non Finnish (NFE) AF: 0.404 AC: 449004 AN: 1110894

Other (OTH) AF: 0.457 AC: 27607 AN: 60368

GnomAD4 genome AF: 0.467 AC: 71032 AN: 152112 Hom.: 17645 Cov.: 33 AF XY: 0.474 AC XY: 35258 AN XY: 74364

African (AFR) AF: 0.507 AC: 21031 AN: 41478

American (AMR) AF: 0.531 AC: 8117 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1458 AN: 3470

East Asian (EAS) AF: 0.923 AC: 4776 AN: 5176

South Asian (SAS) AF: 0.654 AC: 3150 AN: 4818

European-Finnish (FIN) AF: 0.399 AC: 4223 AN: 10592

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26849 AN: 67978

Other (OTH) AF: 0.424 AC: 898 AN: 2116

Alfa AF: 0.425 Hom.: 40638

Bravo AF: 0.479

Asia WGS AF: 0.725 AC: 2518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.094
DANN	Benign	0.64
PhyloP100		-1.4
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: rs4911107; hg19: chr20-31374991;