rs762424

Positions:

• chr21-44259347-A-G
• chr21-44259347-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175867.3(DNMT3L):​c.344+90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,341,542 control chromosomes in the GnomAD database, including 68,376 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 0.37 (11629 hom., cov: 32)
  • Exomes 𝑓: 0.29 (56747 hom.)
• Consequence: DNMT3L NM_175867.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.418

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.344+90T>C		intron_variant		ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.344+90T>C		intron_variant			NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.344+90T>C		intron_variant		1	NM_175867.3	ENSP00000486001	A2
DNMT3L	ENST00000270172.7	c.344+90T>C		intron_variant		1		ENSP00000270172	P4
DNMT3L	ENST00000431166.1	c.299+90T>C		intron_variant		5		ENSP00000400242

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55945 AN: 151912 Hom.: 11596 Cov.: 32

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.295 AC: 350533 AN: 1189512 Hom.: 56747 AF XY: 0.290 AC XY: 172986 AN XY: 596862

Gnomad4 AFR exome AF: 0.531

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.369 AC: 56037 AN: 152030 Hom.: 11629 Cov.: 32 AF XY: 0.371 AC XY: 27597 AN XY: 74302

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.353

Alfa AF: 0.342 Hom.: 1993

Bravo AF: 0.392

Asia WGS AF: 0.406 AC: 1415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.75

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: rs762424; hg19: chr21-45679230;