rs2070565

Variant names:

• chr21-44261270-T-C
• rs2070565
• NM_175867.3:c.-7-4A>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.-7-4A>G variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00004834
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.378
• Publications: 26 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=-0.97).
• 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 rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.-7-4A>G		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.-7-4A>G		splice_region_variant, intron_variant	Intron 1 of 11		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.-7-4A>G		splice_region_variant, intron_variant	Intron 1 of 11	1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.-7-4A>G		splice_region_variant, intron_variant	Intron 1 of 11	1		ENSP00000270172.3
DNMT3L	ENST00000431166.1	c.-7-4A>G		splice_region_variant, intron_variant	Intron 1 of 8	5		ENSP00000400242.1

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

GnomAD2 exomes AF: 0.702 AC: 174482 AN: 248680 AF XY: 0.694

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 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

African (AFR) AF: 0.940 AC: 31440 AN: 33464

American (AMR) AF: 0.710 AC: 31730 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 17293 AN: 26124

East Asian (EAS) AF: 0.778 AC: 30884 AN: 39688

South Asian (SAS) AF: 0.672 AC: 57928 AN: 86208

European-Finnish (FIN) AF: 0.712 AC: 36850 AN: 51724

Middle Eastern (MID) AF: 0.679 AC: 3735 AN: 5498

European-Non Finnish (NFE) AF: 0.656 AC: 729121 AN: 1111334

Other (OTH) AF: 0.684 AC: 41262 AN: 60312

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

African (AFR) AF: 0.927 AC: 38494 AN: 41520

American (AMR) AF: 0.701 AC: 10713 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2368 AN: 3472

East Asian (EAS) AF: 0.798 AC: 4133 AN: 5176

South Asian (SAS) AF: 0.679 AC: 3276 AN: 4828

European-Finnish (FIN) AF: 0.725 AC: 7675 AN: 10592

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44854 AN: 67960

Other (OTH) AF: 0.735 AC: 1554 AN: 2114

Alfa AF: 0.681 Hom.: 122422

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
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070565; hg19: chr21-45681153; COSMIC: COSV54266599;