rs2424913

Variant names:

• chr20-32786453-C-T
• rs2424913
• NM_006892.4:c.307-49C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-32786453-C-T
• chr20-32786453-C-A
• chr20-32786453-C-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_006892.4(DNMT3B):c.307-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.491 (AC=791,704) in the gnomAD database across 1,612,440 control chromosomes, including 205,857 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.99. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23099 hom., cov: 34)
  • Exomes 𝑓: 0.49 (182758 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.347
• Publications: 145 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency-centromeric instability-facial anomalies syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• facioscapulohumeral muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency-centromeric instability-facial anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9903 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006892.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.307-49C>T		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.343-49C>T		intron	N/A	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.307-49C>T		intron	N/A	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.307-49C>T		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.343-49C>T		intron	N/A	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.307-49C>T		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.534	AC:81185	Hom:23061	AN:152096	Cov:34
GnomAD2 exomes	AF: 0.563	AC:140049	Hom:	AN:248646	Cov:
GnomAD4 exome	AF: 0.487	AC:710423	Hom:182758	AN:1460226	Cov:42
GnomAD4 genome	AF: 0.534	AC:81281	Hom:23099	AN:152214	Cov:34
TOPMed (Bravo)	AF: 0.548	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.477	AC:33897	Hom:8379	AN:70994	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.522	AC:1222	Hom:348	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.993	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.460	AC:138	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.508	AC:6603	Hom:	AN:12998	Cov:
GenomeAsia100K	AF: 0.827	AC:2872	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 1.00	AC:7232	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.398	AC:70	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.999	AC:122714	Hom:61319	AN:122808	Cov:
Turkish Variome	AF: 0.451	AC:2986	Hom:712	AN:6626	Cov:
UK10K	AF: 0.448	AC:3385	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.996	AC:8924	Hom:4444	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.454	12890	28420	0.445	12847	28844
SCHEMA(Schizophrenia)	0.449	38113	84898	0.429	58822	137114

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.2
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.53
GPN-Star LLR	N/A	0.24
GPN-Star score	N/A	-0.24
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.35
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2424913;

hg19: chr20-31374259;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar