rs886041398
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003482.4(KMT2D):c.16501C>T(p.Arg5501Ter) 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
KMT2D
NM_003482.4 stop_gained
NM_003482.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.41
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 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-49022063-G-A is Pathogenic according to our data. Variant chr12-49022063-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49022063-G-A is described in Lovd as [Pathogenic]. Variant chr12-49022063-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.16501C>T | p.Arg5501Ter | stop_gained | 54/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.16501C>T | p.Arg5501Ter | stop_gained | 54/55 | 5 | NM_003482.4 | A2 |
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:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Kabuki syndrome 1 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Apr 30, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27302555). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 27302555, 28884922). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000280126/PMID: 20711175). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Jul 12, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2019 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20711175, 25525159, 27302555, 28884922, 29568095) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2023 | - - |
Kabuki syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 280126). This premature translational stop signal has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 2071175, 28884922). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg5501*) in the KMT2D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the KMT2D protein. - |
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
Uncertain
D
MutationTaster
Benign
D
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