rs770315135
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_003482.4(KMT2D):c.1940del(p.Pro647HisfsTer283) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,024,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 28)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
KMT2D
NM_003482.4 frameshift
NM_003482.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.50
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 12-49051742-TG-T is Pathogenic according to our data. Variant chr12-49051742-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547404.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.1940del | p.Pro647HisfsTer283 | frameshift_variant | 11/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.1940del | p.Pro647HisfsTer283 | frameshift_variant | 11/55 | 5 | NM_003482.4 | A2 | |
KMT2D | ENST00000683543.2 | c.1940del | p.Pro647HisfsTer283 | frameshift_variant | 11/56 | P4 | |||
KMT2D | ENST00000685166.1 | c.1940del | p.Pro647HisfsTer283 | frameshift_variant | 10/54 | A2 | |||
KMT2D | ENST00000692637.1 | c.1940del | p.Pro647HisfsTer283 | frameshift_variant | 10/54 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD3 genomes
?
Cov.:
28
GnomAD4 exome AF: 0.0000107 AC: 11AN: 1024634Hom.: 0 Cov.: 35 AF XY: 0.0000117 AC XY: 6AN XY: 514508
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11
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1024634
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35
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514508
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GnomAD4 genome ? Cov.: 28
GnomAD4 genome
?
Cov.:
28
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2023 | Frameshift 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 (gnomAD); This variant is associated with the following publications: (PMID: 36253360, 35904121) - |
Kabuki syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Lung cancer Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Molekularpathologisches Zentrum, Universitaetsklinikum Heidelberg | - | - - |
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