20-32805398-G-T

Position:

• chr20-32805398-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_006892.4(DNMT3B):​c.2292G>T​(p.Arg764Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,846 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R764K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006892.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT3B. . Gene score misZ 1.5 (greater than the threshold 3.09). Trascript score misZ 3.3234 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 20-32805398-G-T is Pathogenic according to our data. Variant chr20-32805398-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461482.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.2292G>T	p.Arg764Ser	missense_variant	21/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.2292G>T	p.Arg764Ser	missense_variant	21/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251464 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 764 of the DNMT3B protein (p.Arg764Ser). This variant is present in population databases (rs759448571, gnomAD 0.003%). This missense change has been observed in individual(s) with centromeric instability and facial anomalies (ICF) syndrome (PMID: 17893117, 23486536; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg756Ser. ClinVar contains an entry for this variant (Variation ID: 461482). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT3B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The DNMT3B c.2292G>T (p.Arg764Ser) variant has been reported in a compound heterozygous state with a frameshift variant in one patient with immunodeficiency-centromeric instability-facial anomalies syndrome (Hagleitner et al. 2008; Weemaes et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional data using isolated T-lymphocytes from the patient carrying the p.Arg764Ser variant show that the T-cell expansion was significantly reduced compared to unrelated controls (Weemaes et al. 2013). The evidence for this variant is limited. The p.Arg764Ser variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for immunodeficiency-centromeric instability-facial anomalies syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.55		Loss of MoRF binding (P = 0.0475);.;.;
MVP		0.98
MPC		2.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

Other links and lift over

dbSNP: rs759448571; hg19: chr20-31393204; COSMIC: COSV52420038;