rs6058885

Variant names:

• chr20-32780142-C-T
• rs6058885
• ENST00000201963.3:c.27C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-32780142-C-T
• chr20-32780142-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_175850.3(DNMT3B):​c.27C>T​(p.Ser9Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,566 control chromosomes in the GnomAD database, including 3,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (654 hom., cov: 31)
  • Exomes 𝑓: 0.062 (3159 hom.)
• Consequence: DNMT3B NM_175850.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.388
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-32780142-C-T is Benign according to our data. Variant chr20-32780142-C-T is described in ClinVar as Benign. ClinVar VariationId is 402792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175850.3. 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.-6-176C>T		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.27C>T	p.Ser9Ser	synonymous	Exon 1 of 22	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_001424359.1		c.27C>T	p.Ser9Ser	synonymous	Exon 1 of 20	NP_001411288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000201963.3	TSL:1	c.27C>T	p.Ser9Ser	synonymous	Exon 1 of 22	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-6-176C>T		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000348286.6	TSL:1	c.-6-176C>T		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12827 AN: 151962 Hom.: 652 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.0744

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0594

Gnomad OTH AF: 0.0689

GnomAD2 exomes AF: 0.0654 AC: 16231 AN: 248260 AF XY: 0.0637

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0745

Gnomad EAS exome AF: 0.0727

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0604

Gnomad OTH exome AF: 0.0654

GnomAD4 exome AF: 0.0622 AC: 90953 AN: 1461486 Hom.: 3159 Cov.: 32 AF XY: 0.0617 AC XY: 44842 AN XY: 727032

African (AFR) AF: 0.149 AC: 4982 AN: 33470

American (AMR) AF: 0.0370 AC: 1653 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 1973 AN: 26116

East Asian (EAS) AF: 0.0848 AC: 3367 AN: 39694

South Asian (SAS) AF: 0.0638 AC: 5503 AN: 86202

European-Finnish (FIN) AF: 0.0708 AC: 3776 AN: 53318

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0586 AC: 65164 AN: 1111864

Other (OTH) AF: 0.0720 AC: 4345 AN: 60380

GnomAD4 genome AF: 0.0845 AC: 12846 AN: 152080 Hom.: 654 Cov.: 31 AF XY: 0.0847 AC XY: 6294 AN XY: 74326

African (AFR) AF: 0.147 AC: 6085 AN: 41484

American (AMR) AF: 0.0457 AC: 699 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3472

East Asian (EAS) AF: 0.0719 AC: 368 AN: 5118

South Asian (SAS) AF: 0.0737 AC: 355 AN: 4820

European-Finnish (FIN) AF: 0.0701 AC: 742 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0594 AC: 4036 AN: 67982

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0632 Hom.: 313

Bravo AF: 0.0849

Asia WGS AF: 0.140 AC: 486 AN: 3478

EpiCase AF: 0.0576

EpiControl AF: 0.0541

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.59
PhyloP100		0.39
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6058885; hg19: chr20-31367948; COSMIC: COSV52419385;