rs875040

Variant names:

• chr20-32795500-C-T
• rs875040
• NM_006892.4:c.1218C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4 BP6_Moderate BP7 BS1

The NM_006892.4(DNMT3B):​c.1218C>T​(p.Asn406Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: DNMT3B NM_006892.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.24
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.261).
• BP6: Variant 20-32795500-C-T is Benign according to our data. Variant chr20-32795500-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 530712.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000263 (40/152284) while in subpopulation AFR AF = 0.000794 (33/41560). AF 95% confidence interval is 0.00058. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1218C>T	p.Asn406Asn	synonymous	Exon 11 of 23	NP_008823.1
	DNMT3B	NM_175850.3		c.1194C>T	p.Asn398Asn	synonymous	Exon 10 of 22	NP_787046.1
	DNMT3B	NM_175848.2		c.1158C>T	p.Asn386Asn	synonymous	Exon 10 of 22	NP_787044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1218C>T	p.Asn406Asn	synonymous	Exon 11 of 23	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.1194C>T	p.Asn398Asn	synonymous	Exon 10 of 22	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.1158C>T	p.Asn386Asn	synonymous	Exon 10 of 20	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251464 AF XY: 0.000118

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727248

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74460

African (AFR) AF: 0.000794 AC: 33 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.83
CADD	Benign	0.036
DANN	Benign	0.78
PhyloP100		-3.2
Mutation Taster		=91/9	polymorphism

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: rs875040; hg19: chr20-31383306;