rs121908943

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_006892.4(DNMT3B):c.1807G>A(p.Ala603Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DNMT3B
NM_006892.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a domain SAM-dependent MTase C5-type (size 278) in uniprot entity DNM3B_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_006892.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the DNMT3B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 33 curated benign missense variants. Gene score misZ: 1.5 (below the threshold of 3.09). Trascript score misZ: 3.3234 (above the threshold of 3.09). GenCC associations: The gene is linked to immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 20-32800200-G-A is Pathogenic according to our data. Variant chr20-32800200-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800200-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4 link	c.1807G>A	p.Ala603Thr	missense_variant	Exon 17 of 23	ENST00000328111.6	NP_008823.1	Q9UBC3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6 link	c.1807G>A	p.Ala603Thr	missense_variant	Exon 17 of 23	1	NM_006892.4	ENSP00000328547.2		Q9UBC3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251496

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Pathogenic:1

Oct 29, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1;C5561960:Facioscapulohumeral muscular dystrophy 4, digenic

Pathogenic:1

Jan 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 603 of the DNMT3B protein (p.Ala603Thr). This variant is present in population databases (rs121908943, gnomAD 0.003%). This missense change has been observed in individual(s) with immunodeficiency, centromeric instability, and facial anomalies syndrome (PMID: 10588719, 28713390; internal data). ClinVar contains an entry for this variant (Variation ID: 6740). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DNMT3B protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 15580563, 16501171). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;.;D

Vest4

0.97

MutPred

0.88

Loss of sheet (P = 0.0817);.;.;.;.;.;

MVP

0.98

MPC

1.8

ClinPred

0.97

GERP RS

5.5

Varity_R

0.91

gMVP

0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over