20-32805997-T-C

Variant names:

• chr20-32805997-T-C
• rs4911263
• NM_006892.4:c.2302-212T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006892.4(DNMT3B):​c.2302-212T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 151,934 control chromosomes in the GnomAD database, including 49,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.80 (49161 hom., cov: 29)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.984
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-32805997-T-C is Benign according to our data. Variant chr20-32805997-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170169.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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.2302-212T>C		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.2278-212T>C		intron	N/A	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.2242-212T>C		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.2302-212T>C		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.2278-212T>C		intron	N/A	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.2172-1765T>C		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120864 AN: 151816 Hom.: 49099 Cov.: 29

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.779

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

GnomAD4 genome AF: 0.796 AC: 120987 AN: 151934 Hom.: 49161 Cov.: 29 AF XY: 0.801 AC XY: 59425 AN XY: 74224

African (AFR) AF: 0.949 AC: 39337 AN: 41468

American (AMR) AF: 0.786 AC: 11997 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2588 AN: 3468

East Asian (EAS) AF: 0.995 AC: 5131 AN: 5158

South Asian (SAS) AF: 0.803 AC: 3851 AN: 4798

European-Finnish (FIN) AF: 0.788 AC: 8301 AN: 10540

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47142 AN: 67928

Other (OTH) AF: 0.779 AC: 1646 AN: 2112

Alfa AF: 0.722 Hom.: 32897

Bravo AF: 0.804

Asia WGS AF: 0.906 AC: 3148 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.77
DANN	Benign	0.32
PhyloP100		-0.98
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: rs4911263; hg19: chr20-31393803;