chr19-2210466-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032482.3(DOT1L):ā€‹c.1072A>Gā€‹(p.Lys358Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,439,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

DOT1L
NM_032482.3 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58
Variant links:
Genes affected
DOT1L (HGNC:24948): (DOT1 like histone lysine methyltransferase) The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29704994).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOT1LNM_032482.3 linkuse as main transcriptc.1072A>G p.Lys358Glu missense_variant 13/28 ENST00000398665.8 NP_115871.1 Q8TEK3-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOT1LENST00000398665.8 linkuse as main transcriptc.1072A>G p.Lys358Glu missense_variant 13/281 NM_032482.3 ENSP00000381657.3 Q8TEK3-2
DOT1LENST00000686010.1 linkuse as main transcriptc.1072A>G p.Lys358Glu missense_variant 13/28 ENSP00000510335.1 A0A8I5QL06

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000139
AC:
2
AN:
1439558
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
715108
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 08, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Benign
-0.055
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.30
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.30
Sift
Uncertain
0.016
D
Sift4G
Benign
0.25
T
Vest4
0.30
MVP
0.25
MPC
0.49
ClinPred
0.90
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.33
gMVP
0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2210465; API