Variant chr21-44258559-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.77

Variant links:

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]

DNMT3L links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3 linkuse as main transcript	c.480G>T	p.Trp160Cys	missense_variant	6/12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4 linkuse as main transcript	c.480G>T	p.Trp160Cys	missense_variant	6/12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3 linkuse as main transcript	c.480G>T	p.Trp160Cys	missense_variant	6/12	1	NM_175867.3	ENSP00000486001	A2	Q9UJW3-1
DNMT3L	ENST00000270172.7 linkuse as main transcript	c.480G>T	p.Trp160Cys	missense_variant	6/12	1		ENSP00000270172	P4	Q9UJW3-2
DNMT3L	ENST00000431166.1 linkuse as main transcript	c.435G>T	p.Trp145Cys	missense_variant	5/9	5		ENSP00000400242

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

222344

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

121192

show subpopulations

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:

AN:

1446280

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718392

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

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

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

.;D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

3.0

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over