chr20-32804971-C-T

Variant names:

• chr20-32804971-C-T
• rs6058893
• NM_006892.4:c.2232-367C>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.2232-367C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,908 control chromosomes in the GnomAD database, including 22,699 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 0.52 (22699 hom., cov: 30)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• Publications: 19 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.88).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.2232-367C>T		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.2208-367C>T		intron	N/A	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.2172-367C>T		intron	N/A	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.2232-367C>T		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.2208-367C>T		intron	N/A	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.2171+2501C>T		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79482 AN: 151788 Hom.: 22673 Cov.: 30

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.524 AC: 79560 AN: 151908 Hom.: 22699 Cov.: 30 AF XY: 0.529 AC XY: 39251 AN XY: 74218

African (AFR) AF: 0.697 AC: 28902 AN: 41440

American (AMR) AF: 0.555 AC: 8479 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1494 AN: 3466

East Asian (EAS) AF: 0.923 AC: 4767 AN: 5164

South Asian (SAS) AF: 0.654 AC: 3151 AN: 4820

European-Finnish (FIN) AF: 0.398 AC: 4191 AN: 10540

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27017 AN: 67910

Other (OTH) AF: 0.481 AC: 1011 AN: 2102

Alfa AF: 0.523 Hom.: 11865

Bravo AF: 0.544

Asia WGS AF: 0.748 AC: 2598 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.70
PhyloP100		0.33
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: rs6058893; hg19: chr20-31392777;