21-44246500-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000628202.3(DNMT3L):​c.1058C>T​(p.Ser353Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 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
ENST00000628202.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.320
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06438649).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNMT3LNM_175867.3 linkuse as main transcriptc.1058C>T p.Ser353Leu missense_variant 12/12 ENST00000628202.3 NP_787063.1
DNMT3LNM_013369.4 linkuse as main transcriptc.1061C>T p.Ser354Leu missense_variant 12/12 NP_037501.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMT3LENST00000628202.3 linkuse as main transcriptc.1058C>T p.Ser353Leu missense_variant 12/121 NM_175867.3 ENSP00000486001 A2Q9UJW3-1
DNMT3LENST00000270172.7 linkuse as main transcriptc.1061C>T p.Ser354Leu missense_variant 12/121 ENSP00000270172 P4Q9UJW3-2
DNMT3LENST00000436357.5 linkuse as main transcriptn.442C>T non_coding_transcript_exon_variant 4/43

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249080
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135004
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000579
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:
0.00000896
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
0
Alfa
AF:
0.0000611
Hom.:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsDec 28, 2022The c.1061C>T (p.S354L) alteration is located in exon 12 (coding exon 11) of the DNMT3L gene. This alteration results from a C to T substitution at nucleotide position 1061, causing the serine (S) at amino acid position 354 to be replaced by a leucine (L). 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
0.084
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
4.6
DANN
Benign
0.72
DEOGEN2
Benign
0.11
.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.064
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
0.34
.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.3
N;.
REVEL
Benign
0.19
Sift
Benign
0.22
T;.
Sift4G
Benign
0.33
T;T
Polyphen
0.023
B;B
Vest4
0.12
MVP
0.55
MPC
0.12
ClinPred
0.022
T
GERP RS
-2.1
Varity_R
0.088
gMVP
0.22

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.

Other links and lift over

dbSNP: rs376151107; hg19: chr21-45666383; API