NM_175867.3:c.480G>A

Variant names:

• chr21-44258559-C-T
• rs958990963
• NM_175867.3:c.480G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_175867.3(DNMT3L):​c.480G>A​(p.Trp160*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000691 in 1,446,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNMT3L NM_175867.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	NM_175867.3	MANE Select	c.480G>A	p.Trp160*	stop_gained	Exon 6 of 12	NP_787063.1	Q9UJW3-1
	DNMT3L	NM_013369.4		c.480G>A	p.Trp160*	stop_gained	Exon 6 of 12	NP_037501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.480G>A	p.Trp160*	stop_gained	Exon 6 of 12	ENSP00000486001.1	Q9UJW3-1
	DNMT3L	ENST00000270172.7	TSL:1	c.480G>A	p.Trp160*	stop_gained	Exon 6 of 12	ENSP00000270172.3	Q9UJW3-2
	DNMT3L	ENST00000431166.1	TSL:5	c.435G>A	p.Trp145*	stop_gained	Exon 5 of 9	ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446280 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718392

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.00 AC: 0 AN: 42354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38940

South Asian (SAS) AF: 0.00 AC: 0 AN: 84338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105192

Other (OTH) AF: 0.00 AC: 0 AN: 59764

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.8
Vest4		0.75
GERP RS		3.7
Mutation Taster		=24/176	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs958990963; hg19: chr21-45678442;