20-32795054-A-G

Variant names:

• chr20-32795054-A-G
• rs6088008
• NM_006892.4:c.1127-355A>G

Variant summary

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

The NM_006892.4(DNMT3B):​c.1127-355A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,032 control chromosomes in the GnomAD database, including 13,142 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 (13142 hom., cov: 32)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• Publications: 8 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=-0.85).
• 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.1127-355A>G		intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.1103-355A>G		intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.1067-355A>G		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.1127-355A>G		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.1103-355A>G		intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.1067-355A>G		intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60028 AN: 151914 Hom.: 13130 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.380

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.395 AC: 60057 AN: 152032 Hom.: 13142 Cov.: 32 AF XY: 0.403 AC XY: 29941 AN XY: 74320

African (AFR) AF: 0.300 AC: 12449 AN: 41456

American (AMR) AF: 0.501 AC: 7655 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3472

East Asian (EAS) AF: 0.921 AC: 4767 AN: 5176

South Asian (SAS) AF: 0.608 AC: 2928 AN: 4816

European-Finnish (FIN) AF: 0.382 AC: 4035 AN: 10566

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25479 AN: 67960

Other (OTH) AF: 0.381 AC: 804 AN: 2110

Alfa AF: 0.394 Hom.: 2029

Bravo AF: 0.401

Asia WGS AF: 0.680 AC: 2363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.80
DANN	Benign	0.73
PhyloP100		0.018
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: rs6088008; hg19: chr20-31382860;