rs2424922

Variant names:

• chr20-32798643-T-C
• rs2424922
• NM_006892.4:c.1674T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-32798643-T-C
• chr20-32798643-T-A
• chr20-32798643-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006892.4(DNMT3B):​c.1674T>C​(p.Tyr558Tyr) 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 NM_006892.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -2.83
• Publications: 29 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 -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 VariationId is 338171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1674T>C	p.Tyr558Tyr	splice_region synonymous	Exon 15 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.1650T>C	p.Tyr550Tyr	splice_region synonymous	Exon 14 of 22	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.1614T>C	p.Tyr538Tyr	splice_region synonymous	Exon 14 of 22	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.1674T>C	p.Tyr558Tyr	splice_region synonymous	Exon 15 of 23	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.1650T>C	p.Tyr550Tyr	splice_region synonymous	Exon 14 of 22	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.1614T>C	p.Tyr538Tyr	splice_region synonymous	Exon 14 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91318 AN: 152130 Hom.: 30388 Cov.: 35

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

GnomAD2 exomes AF: 0.585 AC: 141045 AN: 241166 AF XY: 0.570

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 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.: 60 AF XY: 0.497 AC XY: 361032 AN XY: 726684

African (AFR) AF: 0.866 AC: 28977 AN: 33474

American (AMR) AF: 0.718 AC: 32051 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13355 AN: 26128

East Asian (EAS) AF: 0.999 AC: 39638 AN: 39694

South Asian (SAS) AF: 0.655 AC: 56447 AN: 86214

European-Finnish (FIN) AF: 0.456 AC: 24062 AN: 52788

Middle Eastern (MID) AF: 0.459 AC: 2612 AN: 5694

European-Non Finnish (NFE) AF: 0.444 AC: 494169 AN: 1111846

Other (OTH) AF: 0.534 AC: 32203 AN: 60360

GnomAD4 genome AF: 0.601 AC: 91432 AN: 152248 Hom.: 30442 Cov.: 35 AF XY: 0.605 AC XY: 45034 AN XY: 74464

African (AFR) AF: 0.857 AC: 35616 AN: 41566

American (AMR) AF: 0.600 AC: 9190 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1776 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5145 AN: 5180

South Asian (SAS) AF: 0.686 AC: 3315 AN: 4834

European-Finnish (FIN) AF: 0.452 AC: 4796 AN: 10600

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29777 AN: 67972

Other (OTH) AF: 0.550 AC: 1162 AN: 2114

Alfa AF: 0.499 Hom.: 29991

Bravo AF: 0.624

Asia WGS AF: 0.842 AC: 2924 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.426

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (2)
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.012
DANN	Benign	0.41
PhyloP100		-2.8
Mutation Taster		=53/47	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2424922; hg19: chr20-31386449; COSMIC: COSV52414716;