Variant chr21-44249057-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_175867.3(DNMT3L):c.964C>T(p.Arg322Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Consequence

DNMT3L
NM_175867.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.158

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3 linkuse as main transcript	c.964C>T	p.Arg322Cys	missense_variant	11/12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4 linkuse as main transcript	c.964C>T	p.Arg322Cys	missense_variant	11/12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3 linkuse as main transcript	c.964C>T	p.Arg322Cys	missense_variant	11/12	1	NM_175867.3	ENSP00000486001	A2	Q9UJW3-1
DNMT3L	ENST00000270172.7 linkuse as main transcript	c.964C>T	p.Arg322Cys	missense_variant	11/12	1		ENSP00000270172	P4	Q9UJW3-2
DNMT3L	ENST00000436357.5 linkuse as main transcript	n.348C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247930

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134234

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

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

Mar 01, 2024

The c.964C>T (p.R322C) alteration is located in exon 11 (coding exon 10) of the DNMT3L gene. This alteration results from a C to T substitution at nucleotide position 964, causing the arginine (R) at amino acid position 322 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

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0092

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.12

Sift

Benign

0.072

T;.

Sift4G

Uncertain

0.031

D;D

Polyphen

1.0

D;D

Vest4

0.55

MutPred

0.47

Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);

MVP

0.47

MPC

0.62

ClinPred

0.54

GERP RS

-3.6

Varity_R

0.17

gMVP

0.61

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