rs2276248

Positions:

• chr21-44259375-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3L	NM_175867.3	c.344+62A>G		intron_variant		ENST00000628202.3
DNMT3L	NM_013369.4	c.344+62A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3L	ENST00000628202.3	c.344+62A>G		intron_variant		1	NM_175867.3	A2
DNMT3L	ENST00000270172.7	c.344+62A>G		intron_variant		1		P4
DNMT3L	ENST00000431166.1	c.299+62A>G		intron_variant		5

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

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0708

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.0475

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0427

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

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0499

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.0540

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0626

Alfa AF: 0.0398 Hom.: 118

Bravo AF: 0.0688

Asia WGS AF: 0.157 AC: 544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.076
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs2276248; hg19: chr21-45679258; COSMIC: COSV54266316;