rs958990963

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-44258559-C-A
• chr21-44258559-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_175867.3(DNMT3L):​c.480G>T​(p.Trp160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,446,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DNMT3L NM_175867.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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>T	p.Trp160Cys	missense	Exon 6 of 12	NP_787063.1	Q9UJW3-1
	DNMT3L	NM_013369.4		c.480G>T	p.Trp160Cys	missense	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>T	p.Trp160Cys	missense	Exon 6 of 12	ENSP00000486001.1	Q9UJW3-1
	DNMT3L	ENST00000270172.7	TSL:1	c.480G>T	p.Trp160Cys	missense	Exon 6 of 12	ENSP00000270172.3	Q9UJW3-2
	DNMT3L	ENST00000431166.1	TSL:5	c.435G>T	p.Trp145Cys	missense	Exon 5 of 9	ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000135 AC: 3 AN: 222344 AF XY: 0.00000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000306

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1446280 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 718392

African (AFR) AF: 0.0000301 AC: 1 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: 0.00 AC: 0 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: 0.0000199 AC: 22 AN: 1105192

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.77		Gain of disorder (P = 0.0452)
MVP		0.91
MPC		0.79
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.86
gMVP		0.92
Mutation Taster		=52/48	polymorphism

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: rs958990963; hg19: chr21-45678442;