NM_006892.4:c.290G>C

Variant names:

• chr20-32784843-G-C
• rs200902224
• NM_006892.4:c.290G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006892.4(DNMT3B):​c.290G>C​(p.Arg97Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11565134).

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.290G>C	p.Arg97Pro	missense	Exon 4 of 23	NP_008823.1
	DNMT3B	NM_175850.3		c.326G>C	p.Arg109Pro	missense	Exon 4 of 22	NP_787046.1
	DNMT3B	NM_175848.2		c.290G>C	p.Arg97Pro	missense	Exon 4 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.290G>C	p.Arg97Pro	missense	Exon 4 of 23	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.326G>C	p.Arg109Pro	missense	Exon 4 of 22	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.290G>C	p.Arg97Pro	missense	Exon 4 of 20	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.25	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.23		Loss of MoRF binding (P = 0.001)
MVP		0.75
MPC		0.37
ClinPred		0.17	T
GERP RS		2.0
Varity_R		0.23
gMVP		0.31
Mutation Taster		=79/21	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: rs200902224; hg19: chr20-31372649;