rs281865469
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_015443.4(KANSL1):c.1816C>T(p.Arg606Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R606R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KANSL1
NM_015443.4 stop_gained
NM_015443.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]
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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 17-46066569-G-A is Pathogenic according to our data. Variant chr17-46066569-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KANSL1 | NM_015443.4 | c.1816C>T | p.Arg606Ter | stop_gained | 6/15 | ENST00000432791.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KANSL1 | ENST00000432791.7 | c.1816C>T | p.Arg606Ter | stop_gained | 6/15 | 1 | NM_015443.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461296Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726920
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1461296
Hom.:
Cov.:
32
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AC XY:
0
AN XY:
726920
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
EpiCase
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EpiControl
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Koolen-de Vries syndrome Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jun 05, 2019 | This variant is interpreted as a Pathogenic for Koolen-De Vries syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6: Assumed de novo, but without confirmation of paternity and maternity. PVS1: Predicted nullvariant in a gene where LOF is a known mechanism of disease. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 29, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change creates a premature translational stop signal (p.Arg606*) in the KANSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KANSL1 are known to be pathogenic (PMID: 22544363, 22544367). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Koolen-de Vries syndrome (PMID: 22544367). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 31693). For these reasons, this variant has been classified as Pathogenic. - |
Global developmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Nov 01, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 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 at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22544367, 26293599) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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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