Variant chr21-44260801-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_175867.3(DNMT3L):c.145A>G(p.Ile49Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DNMT3L
NM_175867.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	3/12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	3/12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	3/12	1	NM_175867.3	ENSP00000486001	A2	Q9UJW3-1
DNMT3L	ENST00000270172.7 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	3/12	1		ENSP00000270172	P4	Q9UJW3-2
DNMT3L	ENST00000431166.1 linkuse as main transcript	c.106+353A>G		intron_variant		5		ENSP00000400242

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250830

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460974

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726746

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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

Feb 23, 2023

The c.145A>G (p.I49V) alteration is located in exon 3 (coding exon 2) of the DNMT3L gene. This alteration results from a A to G substitution at nucleotide position 145, causing the isoleucine (I) at amino acid position 49 to be replaced by a valine (V). 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

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Uncertain

0.091

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.78

N;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0040

D;.

Sift4G

Benign

0.098

T;T

Polyphen

0.89

P;P

Vest4

0.48

MutPred

0.44

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.77

MPC

0.24

ClinPred

0.68

GERP RS

3.6

Varity_R

0.31

gMVP

0.36

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

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