rs1555188379
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003482.4(KMT2D):c.11944C>T(p.Arg3982Ter) 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: 33)
Consequence
KMT2D
NM_003482.4 stop_gained
NM_003482.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.28
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]
Genome browser will be placed here
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 12-49032761-G-A is Pathogenic according to our data. Variant chr12-49032761-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49032761-G-A is described in Lovd as [Pathogenic]. Variant chr12-49032761-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.11944C>T | p.Arg3982Ter | stop_gained | 40/55 | ENST00000301067.12 | NP_003473.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.11944C>T | p.Arg3982Ter | stop_gained | 40/55 | 5 | NM_003482.4 | ENSP00000301067 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 47
GnomAD4 exome
Cov.:
47
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Kabuki syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 25, 2021 | This variant has been observed in individual(s) with Kabuki syndrome (PMID: 21280141, 30107592). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 520944). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg3982*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. - |
Kabuki syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Autoinflammatory diseases unit, CHU de Montpellier | Jul 09, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2024 | 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21280141, 27302555, 23913813, 30107592, Fan2020[Article]) - |
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
A
Vest4
GERP RS
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