NM_006892.4:c.-6-8305C>T

Variant names:

• chr20-32772013-C-T
• rs2424907
• NM_006892.4:c.-6-8305C>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.-6-8305C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 152,078 control chromosomes in the GnomAD database, including 30,987 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 0.60 (30987 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• Publications: 5 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-6-8305C>T		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.-6-8305C>T		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91890 AN: 151960 Hom.: 30932 Cov.: 32

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.605 AC: 92006 AN: 152078 Hom.: 30987 Cov.: 32 AF XY: 0.609 AC XY: 45286 AN XY: 74342

African (AFR) AF: 0.872 AC: 36197 AN: 41500

American (AMR) AF: 0.602 AC: 9182 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1810 AN: 3472

East Asian (EAS) AF: 0.993 AC: 5137 AN: 5172

South Asian (SAS) AF: 0.687 AC: 3312 AN: 4824

European-Finnish (FIN) AF: 0.452 AC: 4775 AN: 10568

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29766 AN: 67970

Other (OTH) AF: 0.554 AC: 1168 AN: 2110

Alfa AF: 0.542 Hom.: 4126

Bravo AF: 0.630

Asia WGS AF: 0.843 AC: 2930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.51
DANN	Benign	0.20
PhyloP100		-0.16
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: rs2424907; hg19: chr20-31359819;