rs1057519595
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003482.4(KMT2D):βc.2994delβ(p.Met999Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Consequence
KMT2D
NM_003482.4 frameshift
NM_003482.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.15
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 12-49050593-TA-T is Pathogenic according to our data. Variant chr12-49050593-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 375634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.2994del | p.Met999Ter | frameshift_variant | 12/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.2994del | p.Met999Ter | frameshift_variant | 12/55 | 5 | NM_003482.4 | A2 | |
KMT2D | ENST00000683543.2 | c.2994del | p.Met999Ter | frameshift_variant | 12/56 | P4 | |||
KMT2D | ENST00000685166.1 | c.2994del | p.Met999Ter | frameshift_variant | 11/54 | A2 | |||
KMT2D | ENST00000692637.1 | c.2994del | p.Met999Ter | frameshift_variant | 11/54 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151298Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 34
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GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151298Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73876
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Kabuki syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Nov 19, 2015 | - - |
Kabuki syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2019 | This sequence change creates a premature translational stop signal (p.Met999*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Kabuki syndrome (PMID: 27353043). ClinVar contains an entry for this variant (Variation ID: 375634). Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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