Genetic Variant NM_006892.4:c.273C>G (chr20-32784826-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006892.4(DNMT3B):c.273C>G(p.Phe91Leu) 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. F91F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

DNMT3B
NM_006892.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.288

Publications

1 publications found

Variant links:

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

DNMT3B links:

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ACMG classification

Classification was made for transcript

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=0.1656856).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3B	NM_006892.4	MANE Select	c.273C>G	p.Phe91Leu	missense	Exon 4 of 23	NP_008823.1	Q9UBC3-1
DNMT3B	NM_175850.3		c.309C>G	p.Phe103Leu	missense	Exon 4 of 22	NP_787046.1	Q9UBC3-6
DNMT3B	NM_175848.2		c.273C>G	p.Phe91Leu	missense	Exon 4 of 22	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.273C>G	p.Phe91Leu	missense	Exon 4 of 23	ENSP00000328547.2	Q9UBC3-1
DNMT3B	ENST00000201963.3	TSL:1	c.309C>G	p.Phe103Leu	missense	Exon 4 of 22	ENSP00000201963.3	Q9UBC3-6
DNMT3B	ENST00000348286.6	TSL:1	c.273C>G	p.Phe91Leu	missense	Exon 4 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251382

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.86

M_CAP

Benign

0.063

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.69

PhyloP100

-0.29

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.36

Sift

Benign

0.077

Sift4G

Benign

0.65

Polyphen

0.24

Vest4

0.42

MutPred

0.30

Loss of loop (P = 0.1242)

MVP

0.75

MPC

0.24

ClinPred

0.14

GERP RS

3.1

Varity_R

0.11

gMVP

0.22

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over