rs143589497
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_015443.4(KANSL1):c.1157G>T(p.Ser386Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 35)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
KANSL1
NM_015443.4 missense
NM_015443.4 missense
Scores
3
10
3
Clinical Significance
Conservation
PhyloP100: 7.36
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 Likely_benign. Variant got -5 ACMG points.
BP6
?
Variant 17-46170987-C-A is Benign according to our data. Variant chr17-46170987-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536295.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr17-46170987-C-A is described in Lovd as [Benign].
BS2
?
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KANSL1 | NM_015443.4 | c.1157G>T | p.Ser386Ile | missense_variant | 2/15 | ENST00000432791.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KANSL1 | ENST00000432791.7 | c.1157G>T | p.Ser386Ile | missense_variant | 2/15 | 1 | NM_015443.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152238Hom.: 0 Cov.: 35
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GnomAD4 exome AF: 0.000110 AC: 161AN: 1461810Hom.: 0 Cov.: 30 AF XY: 0.000114 AC XY: 83AN XY: 727210
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152238Hom.: 0 Cov.: 35 AF XY: 0.0000807 AC XY: 6AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 05, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2020 | This variant is associated with the following publications: (PMID: 22544363) - |
Koolen-de Vries syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2021 | Due to the possible presence of a polymorphic segmental duplication, the location of the variant could not be unambiguously resolved. Variants with ambiguous mapping are still reported relative to the KANSL1 transcript. This sequence change replaces serine with isoleucine at codon 386 of the KANSL1 or 17q21.31 segmental duplication protein (p.Ser386Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with KANSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 536295). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Until the location of this sequence change can be resolved, the clinical significance of this variant remains uncertain. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.;D;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;D;.;.;.
Sift4G
Uncertain
D;D;D;.;D;D;.;.;.
Vest4
MVP
MPC
0.15
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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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