rs2070565

Positions:

• chr21-44261270-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.-7-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,611,192 control chromosomes in the GnomAD database, including 375,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (43656 hom., cov: 33)
  • Exomes 𝑓: 0.67 (331674 hom.)
• Consequence: DNMT3L NM_175867.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004834
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.378

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.-7-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.-7-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.-7-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_175867.3	ENSP00000486001	A2
DNMT3L	ENST00000270172.7	c.-7-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000270172	P4
DNMT3L	ENST00000431166.1	c.-7-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000400242

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113692 AN: 152028 Hom.: 43592 Cov.: 33

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.733

GnomAD3 exomes AF: 0.702 AC: 174482 AN: 248680 Hom.: 62031 AF XY: 0.694 AC XY: 93673 AN XY: 135048

Gnomad AFR exome AF: 0.932

Gnomad AMR exome AF: 0.708

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.677

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.672 AC: 980243 AN: 1459046 Hom.: 331674 Cov.: 38 AF XY: 0.671 AC XY: 486891 AN XY: 725888

Gnomad4 AFR exome AF: 0.940

Gnomad4 AMR exome AF: 0.710

Gnomad4 ASJ exome AF: 0.662

Gnomad4 EAS exome AF: 0.778

Gnomad4 SAS exome AF: 0.672

Gnomad4 FIN exome AF: 0.712

Gnomad4 NFE exome AF: 0.656

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.748 AC: 113817 AN: 152146 Hom.: 43656 Cov.: 33 AF XY: 0.749 AC XY: 55735 AN XY: 74382

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.682

Gnomad4 EAS AF: 0.798

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.725

Gnomad4 NFE AF: 0.660

Gnomad4 OTH AF: 0.735

Alfa AF: 0.673 Hom.: 53890

Bravo AF: 0.756

Asia WGS AF: 0.769 AC: 2675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.80
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs2070565; hg19: chr21-45681153; COSMIC: COSV54266599;