chr20-32771303-T-C

Variant names:

• chr20-32771303-T-C
• rs2424906
• NM_006892.4:c.-7+8604T>C

Variant summary

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

The NM_006892.4(DNMT3B):​c.-7+8604T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 151,942 control chromosomes in the GnomAD database, including 27,839 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 0.58 (27839 hom., cov: 31)
• Consequence: DNMT3B NM_006892.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.936
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.-7+8604T>C		intron_variant	Intron 1 of 22	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.-7+8604T>C		intron_variant	Intron 1 of 22	1	NM_006892.4	ENSP00000328547.2

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87875 AN: 151824 Hom.: 27796 Cov.: 31

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.524

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

GnomAD4 genome AF: 0.579 AC: 87976 AN: 151942 Hom.: 27839 Cov.: 31 AF XY: 0.584 AC XY: 43352 AN XY: 74234

African (AFR) AF: 0.789 AC: 32694 AN: 41440

American (AMR) AF: 0.588 AC: 8976 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1765 AN: 3470

East Asian (EAS) AF: 0.993 AC: 5141 AN: 5176

South Asian (SAS) AF: 0.685 AC: 3297 AN: 4812

European-Finnish (FIN) AF: 0.452 AC: 4754 AN: 10520

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29596 AN: 67940

Other (OTH) AF: 0.525 AC: 1109 AN: 2114

Alfa AF: 0.540 Hom.: 19342

Bravo AF: 0.599

Asia WGS AF: 0.832 AC: 2891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.9
DANN	Benign	0.85
PhyloP100		0.94
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: rs2424906; hg19: chr20-31359109;