rs141216815

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000321117.10(DNMT3A):​c.2151C>T​(p.Asn717=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,614,262 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00093 ( 1 hom. )

Consequence

DNMT3A
ENST00000321117.10 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.666
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 2-25240662-G-A is Benign according to our data. Variant chr2-25240662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.666 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000735 (112/152370) while in subpopulation AMR AF= 0.00183 (28/15310). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNMT3ANM_022552.5 linkuse as main transcriptc.2151C>T p.Asn717= synonymous_variant 18/23 ENST00000321117.10 NP_072046.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMT3AENST00000321117.10 linkuse as main transcriptc.2151C>T p.Asn717= synonymous_variant 18/231 NM_022552.5 ENSP00000324375 P3Q9Y6K1-1

Frequencies

GnomAD3 genomes
AF:
0.000742
AC:
113
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.000985
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000664
AC:
167
AN:
251444
Hom.:
0
AF XY:
0.000751
AC XY:
102
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00121
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00104
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000932
AC:
1363
AN:
1461892
Hom.:
1
Cov.:
33
AF XY:
0.000952
AC XY:
692
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000335
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00154
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00104
Gnomad4 OTH exome
AF:
0.000795
GnomAD4 genome
AF:
0.000735
AC:
112
AN:
152370
Hom.:
0
Cov.:
33
AF XY:
0.000711
AC XY:
53
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000985
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00104
Hom.:
0
Bravo
AF:
0.000884
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00115
EpiControl
AF:
0.00119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJul 05, 2019- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024DNMT3A: BP4, BP7, BS1 -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 25, 2017- -
DNMT3A-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 17, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Tatton-Brown-Rahman overgrowth syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
7.4
DANN
Benign
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs141216815; hg19: chr2-25463531; COSMIC: COSV53042018; COSMIC: COSV53042018; API