rs1553412880
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_022552.5(DNMT3A):c.1510delC(p.Leu504TrpfsTer147) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DNMT3A
NM_022552.5 frameshift
NM_022552.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.18
Publications
0 publications found
Genes affected
DNMT3A (HGNC:2978): (DNA methyltransferase 3 alpha) 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 DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]
DNMT3A Gene-Disease associations (from GenCC):
- Tatton-Brown-Rahman overgrowth syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
- Heyn-Sproul-Jackson syndromeInheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-25245296-AG-A is Pathogenic according to our data. Variant chr2-25245296-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 541936.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_022552.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNMT3A | MANE Select | c.1510delC | p.Leu504TrpfsTer147 | frameshift | Exon 13 of 23 | NP_072046.2 | |||
| DNMT3A | c.1510delC | p.Leu504TrpfsTer147 | frameshift | Exon 13 of 23 | NP_783328.1 | Q9Y6K1-1 | |||
| DNMT3A | c.1054delC | p.Leu352TrpfsTer147 | frameshift | Exon 8 of 18 | NP_001307822.1 | Q9Y6K1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DNMT3A | TSL:1 MANE Select | c.1510delC | p.Leu504TrpfsTer147 | frameshift | Exon 13 of 23 | ENSP00000324375.5 | Q9Y6K1-1 | ||
| DNMT3A | TSL:1 | c.1510delC | p.Leu504TrpfsTer147 | frameshift | Exon 13 of 23 | ENSP00000264709.3 | Q9Y6K1-1 | ||
| DNMT3A | TSL:1 | c.943delC | p.Leu315TrpfsTer147 | frameshift | Exon 9 of 19 | ENSP00000370122.4 | Q9Y6K1-2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461638Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727100 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1461638
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
727100
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26090
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86146
European-Finnish (FIN)
AF:
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1111954
Other (OTH)
AF:
AC:
0
AN:
60384
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Tatton-Brown-Rahman overgrowth syndrome (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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