21-44258559-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.480G>T	p.Trp160Cys	missense_variant	Exon 6 of 12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.480G>T	p.Trp160Cys	missense_variant	Exon 6 of 12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.480G>T	p.Trp160Cys	missense_variant	Exon 6 of 12	1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.480G>T	p.Trp160Cys	missense_variant	Exon 6 of 12	1		ENSP00000270172.3
DNMT3L	ENST00000431166.1	c.435G>T	p.Trp145Cys	missense_variant	Exon 5 of 9	5		ENSP00000400242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000135 AC: 3 AN: 222344 Hom.: 0 AF XY: 0.00000825 AC XY: 1 AN XY: 121192

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 SAS 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

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.480G>T (p.W160C) alteration is located in exon 6 (coding exon 5) of the DNMT3L gene. This alteration results from a G to T substitution at nucleotide position 480, causing the tryptophan (W) at amino acid position 160 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-12	D;.;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.77		Gain of disorder (P = 0.0452);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs958990963; hg19: chr21-45678442;