rs879253756
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP6
The NM_001197104.2(KMT2A):c.2633G>A(p.Arg878Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: đť‘“ 0.0000066 ( 0 hom., cov: 31)
Exomes đť‘“: 0.0000027 ( 0 hom. )
Consequence
KMT2A
NM_001197104.2 missense
NM_001197104.2 missense
Scores
5
6
2
Clinical Significance
Conservation
PhyloP100: 9.02
Genes affected
KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]
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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;
PP2
?
Missense variant where missense usually causes diseases, KMT2A
BP6
?
Variant 11-118473792-G-A is Benign according to our data. Variant chr11-118473792-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242909.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2A | NM_001197104.2 | c.2633G>A | p.Arg878Gln | missense_variant | 3/36 | ENST00000534358.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2A | ENST00000534358.8 | c.2633G>A | p.Arg878Gln | missense_variant | 3/36 | 1 | NM_001197104.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152138Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461696Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727138
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Atypical behavior;C1865916:Bilateral ptosis;C4022738:Neurodevelopmental delay Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Apr 13, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2A protein function. ClinVar contains an entry for this variant (Variation ID: 242909). This missense change has been observed in individual(s) with clinical features of KMT2A-related conditions (PMID: 27353043). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 878 of the KMT2A protein (p.Arg878Gln). - |
Language disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand | Jul 09, 2020 | PM2 + PP3 + BS2 + BP1 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;.;D;D;.
Vest4
0.82, 0.63
MutPred
0.24
.;Loss of MoRF binding (P = 0.0415);Loss of MoRF binding (P = 0.0415);.;Loss of MoRF binding (P = 0.0415);
MVP
0.83
MPC
2.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at