20-32791859-C-T

Variant names:

• chr20-32791859-C-T
• rs910084
• NM_006892.4:c.921+151C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006892.4(DNMT3B):​c.921+151C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 759,854 control chromosomes in the GnomAD database, including 78,896 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13225 hom., cov: 32)
  • Exomes 𝑓: 0.44 (65671 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• Publications: 11 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, ClinGen, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	NM_006892.4	MANE Select	c.921+151C>T		intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.957+151C>T		intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.921+151C>T		intron	N/A	NP_787044.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.921+151C>T		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.957+151C>T		intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.921+151C>T		intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60200 AN: 151900 Hom.: 13213 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.437 AC: 265681 AN: 607836 Hom.: 65671 AF XY: 0.443 AC XY: 141530 AN XY: 319314

African (AFR) AF: 0.304 AC: 5053 AN: 16610

American (AMR) AF: 0.635 AC: 20667 AN: 32566

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 7812 AN: 18518

East Asian (EAS) AF: 0.913 AC: 28861 AN: 31612

South Asian (SAS) AF: 0.591 AC: 35723 AN: 60490

European-Finnish (FIN) AF: 0.380 AC: 12601 AN: 33146

Middle Eastern (MID) AF: 0.363 AC: 889 AN: 2450

European-Non Finnish (NFE) AF: 0.370 AC: 140849 AN: 381068

Other (OTH) AF: 0.422 AC: 13226 AN: 31376

GnomAD4 genome AF: 0.396 AC: 60234 AN: 152018 Hom.: 13225 Cov.: 32 AF XY: 0.404 AC XY: 30007 AN XY: 74290

African (AFR) AF: 0.304 AC: 12601 AN: 41454

American (AMR) AF: 0.502 AC: 7673 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1446 AN: 3468

East Asian (EAS) AF: 0.921 AC: 4764 AN: 5174

South Asian (SAS) AF: 0.608 AC: 2931 AN: 4818

European-Finnish (FIN) AF: 0.382 AC: 4029 AN: 10542

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25489 AN: 67968

Other (OTH) AF: 0.383 AC: 809 AN: 2110

Alfa AF: 0.399 Hom.: 2069

Bravo AF: 0.402

Asia WGS AF: 0.683 AC: 2371 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.65
DANN	Benign	0.60
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs910084; hg19: chr20-31379665;