rs2276248

Variant names:

• chr21-44259375-T-C
• rs2276248
• NM_175867.3:c.344+62A>G

Variant summary

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

The NM_175867.3(DNMT3L):​c.344+62A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,519,294 control chromosomes in the GnomAD database, including 3,056 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 0.063 (623 hom., cov: 32)
  • Exomes 𝑓: 0.035 (2433 hom.)
• Consequence: DNMT3L NM_175867.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 5 publications found

Genes affected

DNMT3L (HGNC:2980): (DNA methyltransferase 3 like) 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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175867.3. 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
	DNMT3L	NM_175867.3	MANE Select	c.344+62A>G		intron	N/A	NP_787063.1	Q9UJW3-1
	DNMT3L	NM_013369.4		c.344+62A>G		intron	N/A	NP_037501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.344+62A>G		intron	N/A	ENSP00000486001.1	Q9UJW3-1
	DNMT3L	ENST00000270172.7	TSL:1	c.344+62A>G		intron	N/A	ENSP00000270172.3	Q9UJW3-2
	DNMT3L	ENST00000431166.1	TSL:5	c.299+62A>G		intron	N/A	ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9573 AN: 152032 Hom.: 619 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0589

GnomAD4 exome AF: 0.0346 AC: 47315 AN: 1367144 Hom.: 2433 AF XY: 0.0343 AC XY: 23438 AN XY: 683274

African (AFR) AF: 0.132 AC: 4148 AN: 31462

American (AMR) AF: 0.0708 AC: 3074 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 568 AN: 25340

East Asian (EAS) AF: 0.278 AC: 10843 AN: 38962

South Asian (SAS) AF: 0.0475 AC: 3971 AN: 83618

European-Finnish (FIN) AF: 0.0351 AC: 1824 AN: 51968

Middle Eastern (MID) AF: 0.0375 AC: 183 AN: 4884

European-Non Finnish (NFE) AF: 0.0197 AC: 20267 AN: 1030444

Other (OTH) AF: 0.0427 AC: 2437 AN: 57046

GnomAD4 genome AF: 0.0632 AC: 9618 AN: 152150 Hom.: 623 Cov.: 32 AF XY: 0.0644 AC XY: 4792 AN XY: 74372

African (AFR) AF: 0.124 AC: 5148 AN: 41508

American (AMR) AF: 0.0499 AC: 764 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3468

East Asian (EAS) AF: 0.286 AC: 1481 AN: 5182

South Asian (SAS) AF: 0.0540 AC: 260 AN: 4814

European-Finnish (FIN) AF: 0.0365 AC: 386 AN: 10584

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1338 AN: 67982

Other (OTH) AF: 0.0626 AC: 132 AN: 2110

Alfa AF: 0.0406 Hom.: 174

Bravo AF: 0.0688

Asia WGS AF: 0.157 AC: 544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.076
DANN	Benign	0.72
PhyloP100		-1.8
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: rs2276248; hg19: chr21-45679258; COSMIC: COSV54266316;