chr20-32807671-G-A

Variant names:

• chr20-32807671-G-A
• rs6119286
• NM_006892.4:c.2421-91G>A

Variant summary

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

The NM_006892.4(DNMT3B):​c.2421-91G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,588,240 control chromosomes in the GnomAD database, including 653 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 0.036 (154 hom., cov: 32)
  • Exomes 𝑓: 0.022 (499 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.585
• Publications: 13 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 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.2421-91G>A		intron	N/A	NP_008823.1
	DNMT3B	NM_175850.3		c.2397-91G>A		intron	N/A	NP_787046.1
	DNMT3B	NM_175848.2		c.2361-91G>A		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.2421-91G>A		intron	N/A	ENSP00000328547.2
	DNMT3B	ENST00000201963.3	TSL:1	c.2397-91G>A		intron	N/A	ENSP00000201963.3
	DNMT3B	ENST00000348286.6	TSL:1	c.2172-91G>A		intron	N/A	ENSP00000337764.2

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5412 AN: 152156 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0219 AC: 31403 AN: 1435966 Hom.: 499 AF XY: 0.0219 AC XY: 15706 AN XY: 715734

African (AFR) AF: 0.0856 AC: 2835 AN: 33138

American (AMR) AF: 0.0102 AC: 457 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 69 AN: 26018

East Asian (EAS) AF: 0.00101 AC: 40 AN: 39594

South Asian (SAS) AF: 0.0400 AC: 3416 AN: 85412

European-Finnish (FIN) AF: 0.0168 AC: 744 AN: 44378

Middle Eastern (MID) AF: 0.00700 AC: 40 AN: 5718

European-Non Finnish (NFE) AF: 0.0205 AC: 22461 AN: 1097278

Other (OTH) AF: 0.0224 AC: 1341 AN: 59754

GnomAD4 genome AF: 0.0357 AC: 5437 AN: 152274 Hom.: 154 Cov.: 32 AF XY: 0.0359 AC XY: 2670 AN XY: 74458

African (AFR) AF: 0.0812 AC: 3375 AN: 41552

American (AMR) AF: 0.0153 AC: 234 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.0446 AC: 215 AN: 4826

European-Finnish (FIN) AF: 0.0173 AC: 183 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1324 AN: 68026

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0444 Hom.: 103

Bravo AF: 0.0368

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.35
PhyloP100		-0.58
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: rs6119286; hg19: chr20-31395477;