rs6057648

Variant names:

• chr20-32797074-C-A
• rs6057648
• NM_006892.4:c.1378-113C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-32797074-C-A
• chr20-32797074-C-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.1378-113C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,604,600 control chromosomes in the GnomAD database, including 836 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 0.042 (259 hom., cov: 33)
  • Exomes 𝑓: 0.022 (577 hom.)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 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.1378-113C>A		intron	N/A	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.1354-113C>A		intron	N/A	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.1318-113C>A		intron	N/A	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.1378-113C>A		intron	N/A	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.1354-113C>A		intron	N/A	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.1318-113C>A		intron	N/A	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6344 AN: 152182 Hom.: 257 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0455

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0251 AC: 6041 AN: 240754 AF XY: 0.0248

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00968

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00213

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0224 AC: 32522 AN: 1452300 Hom.: 577 Cov.: 32 AF XY: 0.0224 AC XY: 16183 AN XY: 722758

African (AFR) AF: 0.106 AC: 3562 AN: 33478

American (AMR) AF: 0.0107 AC: 478 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26136

East Asian (EAS) AF: 0.00101 AC: 40 AN: 39698

South Asian (SAS) AF: 0.0402 AC: 3447 AN: 85710

European-Finnish (FIN) AF: 0.0168 AC: 750 AN: 44584

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.0204 AC: 22731 AN: 1111888

Other (OTH) AF: 0.0233 AC: 1405 AN: 60316

GnomAD4 genome AF: 0.0418 AC: 6369 AN: 152300 Hom.: 259 Cov.: 33 AF XY: 0.0413 AC XY: 3077 AN XY: 74460

African (AFR) AF: 0.103 AC: 4275 AN: 41558

American (AMR) AF: 0.0167 AC: 255 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4828

European-Finnish (FIN) AF: 0.0172 AC: 183 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0195 AC: 1326 AN: 68026

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0202 Hom.: 36

Bravo AF: 0.0437

Asia WGS AF: 0.0470 AC: 162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.74
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6057648; hg19: chr20-31384880;