20-32777913-T-C

Variant names:

• chr20-32777913-T-C
• rs6058883
• NM_006892.4:c.-6-2405T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006892.4(DNMT3B):​c.-6-2405T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 152,060 control chromosomes in the GnomAD database, including 29,920 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 (29920 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.-6-2405T>C		intron	N/A	NP_008823.1
	DNMT3B	NM_175848.2		c.-6-2405T>C		intron	N/A	NP_787044.1
	DNMT3B	NM_001424351.1		c.-6-2405T>C		intron	N/A	NP_001411280.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-6-2405T>C		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000348286.6	TSL:1	c.-6-2405T>C		intron	N/A	ENSP00000337764.2
	DNMT3B	ENST00000353855.6	TSL:5	c.-6-2405T>C		intron	N/A	ENSP00000313397.4

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90632 AN: 151942 Hom.: 29870 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.597 AC: 90740 AN: 152060 Hom.: 29920 Cov.: 32 AF XY: 0.601 AC XY: 44704 AN XY: 74328

African (AFR) AF: 0.843 AC: 34985 AN: 41488

American (AMR) AF: 0.600 AC: 9162 AN: 15268

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

East Asian (EAS) AF: 0.993 AC: 5145 AN: 5180

South Asian (SAS) AF: 0.686 AC: 3311 AN: 4824

European-Finnish (FIN) AF: 0.452 AC: 4768 AN: 10558

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29746 AN: 67960

Other (OTH) AF: 0.548 AC: 1155 AN: 2108

Alfa AF: 0.500 Hom.: 38078

Bravo AF: 0.620

Asia WGS AF: 0.841 AC: 2921 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.62
DANN	Benign	0.32
PhyloP100		-1.5
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: rs6058883; hg19: chr20-31365719;