20-32780142-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000201963.3(DNMT3B):​c.27C>G​(p.Ser9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S9S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNMT3B ENST00000201963.3 missense
• Clinical Significance: Not reported in ClinVar
• 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, 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-6-176C>G		intron_variant	Intron 1 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.-6-176C>G		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	14
DANN	Benign	0.96
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.27	D
PhyloP100		0.39
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.26
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.050	T
Polyphen		0.14	B
Vest4		0.16
MutPred		0.15		Loss of phosphorylation at S9 (P = 0.0044);
MVP		0.53
ClinPred		0.089	T
GERP RS		0.45
PromoterAI		0.058	Neutral
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6058885; hg19: chr20-31367948;