20-32800148-C-G

Position:

• chr20-32800148-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006892.4(DNMT3B):​c.1760-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,836 control chromosomes in the GnomAD database, including 212,830 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25798 hom., cov: 33)
  • Exomes 𝑓: 0.49 (187032 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005282
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -2.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-32800148-C-G is Benign according to our data. Variant chr20-32800148-C-G is described in ClinVar as [Benign]. Clinvar id is 338175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32800148-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.1760-5C>G		splice_region_variant, intron_variant		ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.1760-5C>G		splice_region_variant, intron_variant		1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85326 AN: 152010 Hom.: 25767 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.520

GnomAD3 exomes AF: 0.571 AC: 143672 AN: 251480 Hom.: 45055 AF XY: 0.560 AC XY: 76136 AN XY: 135918

Gnomad AFR exome AF: 0.728

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.661

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.491 AC: 718266 AN: 1461708 Hom.: 187032 Cov.: 61 AF XY: 0.494 AC XY: 358865 AN XY: 727164

Gnomad4 AFR exome AF: 0.730

Gnomad4 AMR exome AF: 0.709

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.524

GnomAD4 genome AF: 0.561 AC: 85414 AN: 152128 Hom.: 25798 Cov.: 33 AF XY: 0.567 AC XY: 42125 AN XY: 74360

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.993

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.520

Alfa AF: 0.477 Hom.: 5894

Bravo AF: 0.580

Asia WGS AF: 0.830 AC: 2885 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2019	- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.39
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.010		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: rs1997797; hg19: chr20-31387954;