21-44259476-C-G

Variant summary

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

The NM_175867.3(DNMT3L):ā€‹c.305G>Cā€‹(p.Gly102Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

DNMT3L
NM_175867.3 missense

Scores

2
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.27
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 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
DNMT3LNM_175867.3 linkuse as main transcriptc.305G>C p.Gly102Ala missense_variant 5/12 ENST00000628202.3 NP_787063.1
DNMT3LNM_013369.4 linkuse as main transcriptc.305G>C p.Gly102Ala missense_variant 5/12 NP_037501.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMT3LENST00000628202.3 linkuse as main transcriptc.305G>C p.Gly102Ala missense_variant 5/121 NM_175867.3 ENSP00000486001 A2Q9UJW3-1
DNMT3LENST00000270172.7 linkuse as main transcriptc.305G>C p.Gly102Ala missense_variant 5/121 ENSP00000270172 P4Q9UJW3-2
DNMT3LENST00000431166.1 linkuse as main transcriptc.260G>C p.Gly87Ala missense_variant 4/95 ENSP00000400242

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152182
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000769
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250602
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000326
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:
0.00000753
AC:
11
AN:
1461376
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
726954
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152300
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000494
AC:
6

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 GeneticsApr 17, 2024The c.305G>C (p.G102A) alteration is located in exon 5 (coding exon 4) of the DNMT3L gene. This alteration results from a G to C substitution at nucleotide position 305, causing the glycine (G) at amino acid position 102 to be replaced by an alanine (A). 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
.;D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.049
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Pathogenic
2.9
M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-5.7
D;.;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0020
D;.;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.79
MutPred
0.70
Gain of catalytic residue at G102 (P = 0.1122);Gain of catalytic residue at G102 (P = 0.1122);.;
MVP
0.89
MPC
0.63
ClinPred
0.81
D
GERP RS
4.3
Varity_R
0.81
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs549252923; hg19: chr21-45679359; API