rs2134152310
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_001197104.2(KMT2A):c.69delG(p.Arg24AlafsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,009,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G23G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
KMT2A
NM_001197104.2 frameshift
NM_001197104.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.289
Publications
0 publications found
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]
KMT2A Gene-Disease associations (from GenCC):
- Wiedemann-Steiner syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 448 pathogenic variants in the truncated region.
PP5
Variant 11-118436575-CG-C is Pathogenic according to our data. Variant chr11-118436575-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1343266.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KMT2A | ENST00000534358.8 | c.69delG | p.Arg24AlafsTer4 | frameshift_variant | Exon 1 of 36 | 1 | NM_001197104.2 | ENSP00000436786.2 | ||
| ENSG00000285827 | ENST00000648261.1 | c.-798-32194delG | intron_variant | Intron 1 of 6 | ENSP00000498126.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000892 AC: 9AN: 1009396Hom.: 0 Cov.: 20 AF XY: 0.0000168 AC XY: 8AN XY: 476576 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
9
AN:
1009396
Hom.:
Cov.:
20
AF XY:
AC XY:
8
AN XY:
476576
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:
20690
American (AMR)
AF:
AC:
0
AN:
6680
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
11916
East Asian (EAS)
AF:
AC:
0
AN:
22400
South Asian (SAS)
AF:
AC:
0
AN:
18600
European-Finnish (FIN)
AF:
AC:
5
AN:
26700
Middle Eastern (MID)
AF:
AC:
0
AN:
2892
European-Non Finnish (NFE)
AF:
AC:
2
AN:
860480
Other (OTH)
AF:
AC:
1
AN:
39038
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.236
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Wiedemann-Steiner syndrome Pathogenic:1
Mar 23, 2021
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PVS1, PM2 -
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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