rs6058896

Variant names:

• chr20-32808346-C-T
• rs6058896
• NM_006892.4:c.*443C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006892.4(DNMT3B):​c.*443C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 309,662 control chromosomes in the GnomAD database, including 881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (519 hom., cov: 31)
  • Exomes 𝑓: 0.065 (362 hom.)
• Consequence: DNMT3B NM_006892.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.778
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-32808346-C-T is Benign according to our data. Variant chr20-32808346-C-T is described in ClinVar as Benign. ClinVar VariationId is 338192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 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.*443C>T		3_prime_UTR	Exon 23 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.*443C>T		3_prime_UTR	Exon 22 of 22	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.*443C>T		3_prime_UTR	Exon 22 of 22	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.*443C>T		3_prime_UTR	Exon 23 of 23	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.*443C>T		3_prime_UTR	Exon 22 of 22	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.*443C>T		3_prime_UTR	Exon 20 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11662 AN: 151782 Hom.: 514 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0421

Gnomad ASJ AF: 0.0802

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0676

GnomAD4 exome AF: 0.0648 AC: 10227 AN: 157760 Hom.: 362 Cov.: 0 AF XY: 0.0640 AC XY: 4915 AN XY: 76840

African (AFR) AF: 0.115 AC: 671 AN: 5814

American (AMR) AF: 0.0399 AC: 253 AN: 6338

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 477 AN: 6906

East Asian (EAS) AF: 0.0886 AC: 1321 AN: 14910

South Asian (SAS) AF: 0.0593 AC: 715 AN: 12064

European-Finnish (FIN) AF: 0.0657 AC: 254 AN: 3866

Middle Eastern (MID) AF: 0.0387 AC: 31 AN: 802

European-Non Finnish (NFE) AF: 0.0599 AC: 5759 AN: 96170

Other (OTH) AF: 0.0685 AC: 746 AN: 10890

GnomAD4 genome AF: 0.0770 AC: 11694 AN: 151902 Hom.: 519 Cov.: 31 AF XY: 0.0768 AC XY: 5702 AN XY: 74256

African (AFR) AF: 0.121 AC: 5024 AN: 41358

American (AMR) AF: 0.0419 AC: 640 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0802 AC: 278 AN: 3468

East Asian (EAS) AF: 0.0707 AC: 365 AN: 5166

South Asian (SAS) AF: 0.0771 AC: 371 AN: 4814

European-Finnish (FIN) AF: 0.0687 AC: 725 AN: 10550

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4014 AN: 67974

Other (OTH) AF: 0.0678 AC: 143 AN: 2108

Alfa AF: 0.0738 Hom.: 115

Bravo AF: 0.0768

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		0.78
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: rs6058896; hg19: chr20-31396152;