rs147591633

chr20-32787362-G-Achr20-32787362-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BS1_Supporting

The NM_006892.4(DNMT3B):c.565G>A(p.Ala189Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A189A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (1 hom.)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.91

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DNMT3B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063634217).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000433 (66/152316) while in subpopulation AFR AF= 0.00156 (65/41572). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.565G>A	p.Ala189Thr	missense_variant	6/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.565G>A	p.Ala189Thr	missense_variant	6/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00157

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251292 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135838

Gnomad AFR exome AF: 0.00117

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461884 Hom.: 1 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 727240

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74478

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 02, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 189 of the DNMT3B protein (p.Ala189Thr). This variant is present in population databases (rs147591633, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DNMT3B-related conditions. ClinVar contains an entry for this variant (Variation ID: 461483). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	0.0040
Dann	Benign	0.83
DEOGEN2	Benign	0.054	T;.;.;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.66	T;T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0064	T;T;T;T;T;T
MetaSVM	Uncertain	0.0069	D
MutationAssessor	Benign	0.20	N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.46	T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B
Vest4		0.034
MVP		0.38
MPC		0.17
ClinPred		0.012	T
GERP RS		-7.6
Varity_R		0.026
gMVP		0.22

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

Other links and lift over

dbSNP: rs147591633; hg19: chr20-31375168; COSMIC: COSV52423799;