rs1555038029
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001197104.2(KMT2A):c.3341C>A(p.Ser1114Ter) variant causes a stop gained change involving the alteration of a 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: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KMT2A
NM_001197104.2 stop_gained
NM_001197104.2 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.52
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 12 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 11-118477973-C-A is Pathogenic according to our data. Variant chr11-118477973-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 488383.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2A | NM_001197104.2 | c.3341C>A | p.Ser1114Ter | stop_gained | 5/36 | ENST00000534358.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2A | ENST00000534358.8 | c.3341C>A | p.Ser1114Ter | stop_gained | 5/36 | 1 | NM_001197104.2 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461646Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727148
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1461646
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30
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0
AN XY:
727148
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Wiedemann-Steiner syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 24, 2017 | A heterozygous variant was identified in exon 5 of the KMT2A gene, NM_001197104(KMT2A):c.3341C>A (chr11:118348688). This nonsense variant is predicted to create a change of a serine to a stop at amino acid position 1114, NP_001184033.1(KMT2A):p.(Ser1114*), resulting in a truncated protein. The serine at this position has high conservation and this substitution results in a substantial amino acid truncation which includes important domains of the protein. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort, is not present in population databases and has not been previosuly observed in other clinical cases. However, heterozygous truncating variants are associated with Wiedemann-Steiner syndrome and truncating variants downstream in the KMT2A gene have been reported as pathogenic (ClinVar). Parental testing confirmed this variant to be de novo. Based on current information this variant has been classified as PATHOGENIC. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
0.85, 0.83
GERP RS
Splicing
Name
Calibrated prediction
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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