20-32787505-A-G

Variant names:

• chr20-32787505-A-G
• rs4911108
• NM_006892.4:c.654+54A>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.654+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,568,548 control chromosomes in the GnomAD database, including 147,255 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 0.42 (14148 hom., cov: 33)
  • Exomes 𝑓: 0.42 (133107 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 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.654+54A>G		intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.690+54A>G		intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.654+54A>G		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.654+54A>G		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.690+54A>G		intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.654+54A>G		intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63097 AN: 151984 Hom.: 14127 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.420 AC: 594635 AN: 1416446 Hom.: 133107 AF XY: 0.424 AC XY: 297789 AN XY: 702738

African (AFR) AF: 0.368 AC: 11943 AN: 32416

American (AMR) AF: 0.641 AC: 24492 AN: 38216

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 10770 AN: 25470

East Asian (EAS) AF: 0.914 AC: 34503 AN: 37750

South Asian (SAS) AF: 0.591 AC: 48929 AN: 82854

European-Finnish (FIN) AF: 0.384 AC: 19810 AN: 51594

Middle Eastern (MID) AF: 0.369 AC: 1569 AN: 4250

European-Non Finnish (NFE) AF: 0.384 AC: 417139 AN: 1085146

Other (OTH) AF: 0.434 AC: 25480 AN: 58750

GnomAD4 genome AF: 0.415 AC: 63147 AN: 152102 Hom.: 14148 Cov.: 33 AF XY: 0.422 AC XY: 31381 AN XY: 74342

African (AFR) AF: 0.370 AC: 15356 AN: 41486

American (AMR) AF: 0.509 AC: 7786 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3472

East Asian (EAS) AF: 0.921 AC: 4770 AN: 5180

South Asian (SAS) AF: 0.609 AC: 2935 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4018 AN: 10566

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25510 AN: 67974

Other (OTH) AF: 0.393 AC: 830 AN: 2112

Alfa AF: 0.383 Hom.: 14027

Bravo AF: 0.425

Asia WGS AF: 0.680 AC: 2360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.37
PhyloP100		-0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs4911108; hg19: chr20-31375311;