rs1555194045
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003482.4(KMT2D):c.5269C>T(p.Arg1757Ter) 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
KMT2D
NM_003482.4 stop_gained
NM_003482.4 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 2.17
Genes affected
KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [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 12-49043918-G-A is Pathogenic according to our data. Variant chr12-49043918-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 435669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49043918-G-A is described in Lovd as [Pathogenic]. Variant chr12-49043918-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.5269C>T | p.Arg1757Ter | stop_gained | 23/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.5269C>T | p.Arg1757Ter | stop_gained | 23/55 | 5 | NM_003482.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Kabuki syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital | Feb 28, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 28, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 02, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2021 | 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28991257, 26411453, 22434255, 25142838, 30107592, 32170002, 32368696, 33767182, 33084842, 34539730, 23913813) - |
KMT2D-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 03, 2023 | The KMT2D c.5269C>T variant is predicted to result in premature protein termination (p.Arg1757*). This variant was reported de novo in multiple individuals with Kabuki syndrome (See for example, Table 1, Miyake et al. 2013. PubMed ID: 23913813; Table 2, Lin et al. 2014. PubMed ID: 25142838; Table 4, Martinez-Granero et al. 2021. PubMed ID: 33767182). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in KMT2D are expected to be pathogenic. This variant is interpreted 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
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A
Vest4
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