rs150682895

chr20-32795432-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006892.4(DNMT3B):c.1150G>A(p.Ala384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,144 control chromosomes in the GnomAD database, including 115 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.217

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNMT3B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023308396).
• BP6: Variant 20-32795432-G-A is Benign according to our data. Variant chr20-32795432-G-A is described in ClinVar as [Benign]. Clinvar id is 461480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32795432-G-A is described in Lovd as [Likely_benign]. Variant chr20-32795432-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00952 (1449/152278) while in subpopulation AMR AF= 0.0169 (259/15294). AF 95% confidence interval is 0.0152. There are 6 homozygotes in gnomad4. There are 809 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.1150G>A	p.Ala384Thr	missense_variant	11/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1150G>A	p.Ala384Thr	missense_variant	11/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1450 AN: 152160 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00903 AC: 2271 AN: 251404 Hom.: 17 AF XY: 0.00926 AC XY: 1258 AN XY: 135876

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00934

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0106 AC: 15503 AN: 1461866 Hom.: 109 Cov.: 30 AF XY: 0.0105 AC XY: 7665 AN XY: 727234

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00930

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00351

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00952 AC: 1449 AN: 152278 Hom.: 6 Cov.: 32 AF XY: 0.0109 AC XY: 809 AN XY: 74472

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0109 Hom.: 12

Bravo AF: 0.00896

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00792 AC: 962

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNMT3B: BP4, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	11
Dann	Benign	0.84
DEOGEN2	Benign	0.045	T;.;.;.;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.82	T;T;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.46	N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.86	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.88	T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;B
Vest4		0.14
MVP		0.28
MPC		0.17
ClinPred		0.0054	T
GERP RS		2.7
Varity_R		0.026
gMVP		0.20

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: rs150682895; hg19: chr20-31383238; COSMIC: COSV52424443;