20-32762858-C-G

Variant names:

• chr20-32762858-C-G
• rs742630
• NM_006892.4:c.-7+159C>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.-7+159C>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 151,558 control chromosomes in the GnomAD database, including 27,496 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 (27496 hom., cov: 30)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-7+159C>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.-7+159C>G		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85631 AN: 151442 Hom.: 27449 Cov.: 30

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.566 AC: 85732 AN: 151558 Hom.: 27496 Cov.: 30 AF XY: 0.570 AC XY: 42209 AN XY: 74040

African (AFR) AF: 0.841 AC: 34844 AN: 41430

American (AMR) AF: 0.575 AC: 8775 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1545 AN: 3466

East Asian (EAS) AF: 0.926 AC: 4663 AN: 5036

South Asian (SAS) AF: 0.656 AC: 3145 AN: 4792

European-Finnish (FIN) AF: 0.405 AC: 4257 AN: 10520

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.397 AC: 26896 AN: 67752

Other (OTH) AF: 0.506 AC: 1065 AN: 2104

Alfa AF: 0.229 Hom.: 388

Bravo AF: 0.592

Asia WGS AF: 0.749 AC: 2601 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.64
PhyloP100		-0.017
PromoterAI		0.069	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs742630; hg19: chr20-31350664; COSMIC: COSV60190709;