chr21-44259347-A-G

Variant names:

• chr21-44259347-A-G
• rs762424
• NM_175867.3:c.344+90T>C

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+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
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	NM_175867.3	MANE Select	c.344+90T>C		intron	N/A	NP_787063.1
	DNMT3L	NM_013369.4		c.344+90T>C		intron	N/A	NP_037501.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.344+90T>C		intron	N/A	ENSP00000486001.1
	DNMT3L	ENST00000270172.7	TSL:1	c.344+90T>C		intron	N/A	ENSP00000270172.3
	DNMT3L	ENST00000431166.1	TSL:5	c.299+90T>C		intron	N/A	ENSP00000400242.1

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

African (AFR) AF: 0.531 AC: 14788 AN: 27854

American (AMR) AF: 0.520 AC: 19646 AN: 37774

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 5656 AN: 22974

East Asian (EAS) AF: 0.632 AC: 23675 AN: 37466

South Asian (SAS) AF: 0.204 AC: 15592 AN: 76294

European-Finnish (FIN) AF: 0.309 AC: 15240 AN: 49284

Middle Eastern (MID) AF: 0.298 AC: 1138 AN: 3814

European-Non Finnish (NFE) AF: 0.270 AC: 238852 AN: 883206

Other (OTH) AF: 0.314 AC: 15946 AN: 50846

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

African (AFR) AF: 0.522 AC: 21637 AN: 41446

American (AMR) AF: 0.430 AC: 6568 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 855 AN: 3468

East Asian (EAS) AF: 0.636 AC: 3281 AN: 5160

South Asian (SAS) AF: 0.207 AC: 998 AN: 4826

European-Finnish (FIN) AF: 0.316 AC: 3339 AN: 10576

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18325 AN: 67960

Other (OTH) AF: 0.353 AC: 746 AN: 2112

Alfa AF: 0.392 Hom.: 5777

Bravo AF: 0.392

Asia WGS AF: 0.406 AC: 1415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.75
PhyloP100		0.42
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: rs762424; hg19: chr21-45679230;