rs1555039343
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000534358.8(KMT2A):c.3790C>T(p.Arg1264Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
KMT2A
ENST00000534358.8 stop_gained
ENST00000534358.8 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.02
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 Pathogenic. Variant got 18 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 11-118481870-C-T is Pathogenic according to our data. Variant chr11-118481870-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 522088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118481870-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KMT2A | NM_001197104.2 | c.3790C>T | p.Arg1264Ter | stop_gained | 7/36 | ENST00000534358.8 | NP_001184033.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KMT2A | ENST00000534358.8 | c.3790C>T | p.Arg1264Ter | stop_gained | 7/36 | 1 | NM_001197104.2 | ENSP00000436786 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28600779, 29276005, 31785789) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 30, 2023 | This sequence change creates a premature translational stop signal (p.Arg1264*) in the KMT2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2A are known to be pathogenic (PMID: 22795537, 25810209, 29574747). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of KMT2A-related conditions (PMID: 28600779, 29276005, 31785789). ClinVar contains an entry for this variant (Variation ID: 522088). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Wiedemann-Steiner syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2017 | - - |
Hirsutism;C3714756:Intellectual disability Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Nov 28, 2018 | - - |
Rare genetic intellectual disability Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
0.86, 0.84
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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