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

Variant names:

• chr20-32800145-C-T
• rs2424926
• NM_006892.4:c.1760-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006892.4(DNMT3B):​c.1760-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,614,126 control chromosomes in the GnomAD database, including 100 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (89 hom.)
• Consequence: DNMT3B NM_006892.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003183
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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=-0.8).
• BP6: Variant 20-32800145-C-T is Benign according to our data. Variant chr20-32800145-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.004 (609/152274) while in subpopulation AMR AF = 0.00333 (51/15306). AF 95% confidence interval is 0.00287. There are 11 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

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>T		splice_region intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.1736-8C>T		splice_region intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.1700-8C>T		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>T		splice_region intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.1736-8C>T		splice_region intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.1700-8C>T		splice_region intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152156 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00529 AC: 1330 AN: 251492 AF XY: 0.00530

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0810

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00394 AC: 5755 AN: 1461852 Hom.: 89 Cov.: 30 AF XY: 0.00409 AC XY: 2974 AN XY: 727230

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 2082 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00131 AC: 113 AN: 86256

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53418

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.00264 AC: 2939 AN: 1111988

Other (OTH) AF: 0.00768 AC: 464 AN: 60392

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152274 Hom.: 11 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74452

African (AFR) AF: 0.000650 AC: 27 AN: 41534

American (AMR) AF: 0.00333 AC: 51 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 255 AN: 3472

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68032

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.0105 Hom.: 11

Bravo AF: 0.00447

EpiCase AF: 0.00414

EpiControl AF: 0.00450

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.29
DANN	Benign	0.46
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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;