20-32772577-C-T

Variant names:

• chr20-32772577-C-T
• rs2424908
• NM_006892.4:c.-6-7741C>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.-6-7741C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 150,730 control chromosomes in the GnomAD database, including 6,164 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 0.28 (6164 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 33 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-6-7741C>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.-6-7741C>T		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41411 AN: 150614 Hom.: 6144 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.160

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.275 AC: 41465 AN: 150730 Hom.: 6164 Cov.: 32 AF XY: 0.276 AC XY: 20356 AN XY: 73656

African (AFR) AF: 0.344 AC: 13866 AN: 40316

American (AMR) AF: 0.334 AC: 5075 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 683 AN: 3460

East Asian (EAS) AF: 0.550 AC: 2836 AN: 5152

South Asian (SAS) AF: 0.304 AC: 1464 AN: 4820

European-Finnish (FIN) AF: 0.242 AC: 2553 AN: 10566

Middle Eastern (MID) AF: 0.162 AC: 47 AN: 290

European-Non Finnish (NFE) AF: 0.210 AC: 14285 AN: 67936

Other (OTH) AF: 0.257 AC: 540 AN: 2098

Alfa AF: 0.209 Hom.: 1765

Bravo AF: 0.286

Asia WGS AF: 0.433 AC: 1504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.58
DANN	Benign	0.69
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: rs2424908; hg19: chr20-31360383;