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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 frequency of 0.491 in 1,612,440 control chromosomes in the GnomAD database, including 205,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• facioscapulohumeral muscular dystrophy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-32786453-C-T is Benign according to our data. Variant chr20-32786453-C-T is described in ClinVar as Benign. ClinVar VariationId is 1170168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

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

GnomAD3 genomes AF: 0.534 AC: 81185 AN: 152096 Hom.: 23061 Cov.: 34

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.488

GnomAD2 exomes AF: 0.563 AC: 140049 AN: 248646 AF XY: 0.553

Gnomad AFR exome AF: 0.639

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.487 AC: 710423 AN: 1460226 Hom.: 182758 Cov.: 42 AF XY: 0.489 AC XY: 355196 AN XY: 726446

African (AFR) AF: 0.636 AC: 21290 AN: 33470

American (AMR) AF: 0.698 AC: 31176 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 13055 AN: 26126

East Asian (EAS) AF: 0.999 AC: 39623 AN: 39682

South Asian (SAS) AF: 0.656 AC: 56485 AN: 86168

European-Finnish (FIN) AF: 0.454 AC: 23825 AN: 52464

Middle Eastern (MID) AF: 0.393 AC: 2265 AN: 5766

European-Non Finnish (NFE) AF: 0.442 AC: 491760 AN: 1111504

Other (OTH) AF: 0.513 AC: 30944 AN: 60362

GnomAD4 genome AF: 0.534 AC: 81281 AN: 152214 Hom.: 23099 Cov.: 34 AF XY: 0.540 AC XY: 40167 AN XY: 74416

African (AFR) AF: 0.634 AC: 26347 AN: 41530

American (AMR) AF: 0.570 AC: 8714 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1735 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5147 AN: 5182

South Asian (SAS) AF: 0.685 AC: 3306 AN: 4826

European-Finnish (FIN) AF: 0.451 AC: 4783 AN: 10606

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29581 AN: 67992

Other (OTH) AF: 0.489 AC: 1032 AN: 2112

Alfa AF: 0.477 Hom.: 6501

Bravo AF: 0.548

Asia WGS AF: 0.827 AC: 2872 AN: 3478

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.53
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2424913; hg19: chr20-31374259;