20-32798643-T-C

Position:

chr20-32798643-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000328111.6(DNMT3B):c.1674T>C(p.Tyr558=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,613,114 control chromosomes in the GnomAD database, including 221,643 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 0.60 ( 30442 hom., cov: 35)

Exomes 𝑓: 0.50 ( 191201 hom. )

Consequence

DNMT3B
ENST00000328111.6 splice_region, synonymous

Scores

Splicing: ADA: 0.00005390

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -2.83

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-32798643-T-C is Benign according to our data. Variant chr20-32798643-T-C is described in ClinVar as [Benign]. Clinvar id is 338171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32798643-T-C is described in Lovd as [Benign]. Variant chr20-32798643-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.83 with no splicing effect.

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 linkuse as main transcript	c.1674T>C	p.Tyr558=	splice_region_variant, synonymous_variant	15/23	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6 linkuse as main transcript	c.1674T>C	p.Tyr558=	splice_region_variant, synonymous_variant	15/23	1	NM_006892.4	ENSP00000328547	A2	Q9UBC3-1

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

91318

AN:

152130

Hom.:

30388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.993

Gnomad SAS

AF:

0.687

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.550

GnomAD3 exomes

AF:

0.585

AC:

141045

AN:

241166

Hom.:

45564

AF XY:

0.570

AC XY:

74930

AN XY:

131396

show subpopulations

Gnomad AFR exome

AF:

0.867

Gnomad AMR exome

AF:

0.730

Gnomad ASJ exome

AF:

0.508

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.661

Gnomad FIN exome

AF:

0.455

Gnomad NFE exome

AF:

0.442

Gnomad OTH exome

AF:

0.520

GnomAD4 exome

AF:

0.495

AC:

723514

AN:

1460866

Hom.:

191201

Cov.:

AF XY:

0.497

AC XY:

361032

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.866

Gnomad4 AMR exome

AF:

0.718

Gnomad4 ASJ exome

AF:

0.511

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.655

Gnomad4 FIN exome

AF:

0.456

Gnomad4 NFE exome

AF:

0.444

Gnomad4 OTH exome

AF:

0.534

GnomAD4 genome

AF:

0.601

AC:

91432

AN:

152248

Hom.:

30442

Cov.:

AF XY:

0.605

AC XY:

45034

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.857

Gnomad4 AMR

AF:

0.600

Gnomad4 ASJ

AF:

0.512

Gnomad4 EAS

AF:

0.993

Gnomad4 SAS

AF:

0.686

Gnomad4 FIN

AF:

0.452

Gnomad4 NFE

AF:

0.438

Gnomad4 OTH

AF:

0.550

Alfa

AF:

0.486

Hom.:

21248

Bravo

AF:

0.624

Asia WGS

AF:

0.842

AC:

2924

AN:

3478

EpiCase

AF:

0.430

EpiControl

AF:

0.426

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 provided

Benign:1Other:1

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

-0.82

CADD

Benign

0.012

DANN

Benign

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

dbscSNV1_RF

Benign

0.20

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