NM_006892.4:c.1760-8C>G

Variant names:

• chr20-32800145-C-G
• rs2424926
• NM_006892.4:c.1760-8C>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.1760-8C>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 0.00363 in 1,614,128 control chromosomes in the GnomAD database, including 149 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 0.018 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (74 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002089
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.14
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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=-0.82).
• BP6: Variant 20-32800145-C-G is Benign according to our data. Variant chr20-32800145-C-G is described in ClinVar as Benign. ClinVar VariationId is 338173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 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.1760-8C>G		splice_region intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.1736-8C>G		splice_region intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.1700-8C>G		splice_region intron	N/A	NP_787044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1760-8C>G		splice_region intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.1736-8C>G		splice_region intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.1700-8C>G		splice_region intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152142 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00483 AC: 1215 AN: 251492 AF XY: 0.00360

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00212 AC: 3093 AN: 1461868 Hom.: 74 Cov.: 30 AF XY: 0.00184 AC XY: 1340 AN XY: 727238

African (AFR) AF: 0.0655 AC: 2194 AN: 33480

American (AMR) AF: 0.00344 AC: 154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1111998

Other (OTH) AF: 0.00508 AC: 307 AN: 60392

GnomAD4 genome AF: 0.0181 AC: 2759 AN: 152260 Hom.: 75 Cov.: 33 AF XY: 0.0174 AC XY: 1293 AN XY: 74444

African (AFR) AF: 0.0622 AC: 2584 AN: 41520

American (AMR) AF: 0.00751 AC: 115 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68032

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00105 Hom.: 11

Bravo AF: 0.0211

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)
-	-	1	DNMT3B-related disorder (1)
-	-	1	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.45
DANN	Benign	0.47
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.064
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: rs2424926; hg19: chr20-31387951;